Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

Introduction

In 2023, the American Cancer Society estimated that there will be nearly 2 million new cancer cases and 609,000 cancer deaths in the United States [ 1 ]. According to the statistics, the number of cancer cases is increasing but the cancer mortality rate is decreasing year by year globally, it is particularly reflected by leukemia cancer, melanoma and kidney cancer [ 1 ]. The global cancer incidence in 2020 indicated that female breast cancer (BC) has surpassed lung adenocarcinoma (LUAD) and become the most common cancer [ 2 ]. The incidence of BC, prostate cancer (PC) and endometrial carcinoma (EC) are increasing and the treatment option of cancer is still scarce [ 2 ]. Currently available cancer treatment strategies include surgery, radiation therapy, systemic chemotherapy and biological therapy. Surgery is the traditional treatment for cancer and is the most effective way to eliminate multiple cancers before they develop lymph node or distant metastasis [ 3 ]. Radiation therapy preferentially kills rapidly dividing cells and cells that are difficult to repair their own DNA, and cancer cells are more likely to be targeted than normal cells [ 4 ]. Systemic chemotherapy affects the growth ability of cells by applying drugs, which are usually destructive to rapidly growing cancer cells, [ 5 ]. Targeted therapy including both small molecule compounds and antibodies, blocks cancer cell growth by specifically targeting molecules required for cell growth and tumourigenesis [ 6 ]. Biologic therapy is committed to stimulating the host immune response, thereby achieving long-term killing of tumors [ 7 ]. In addition, there is an adjuvant therapy-hormone therapy, which is applied to tumors depend on androgens or estrogens for growth, such as BC and PC. These drugs, such as tamoxifen, anastrozole, exemestane, blocks hormonal signals, thereby stimulating cancer cells to die [ 8 ]. These treatment strategies can be combined to complement each other to treat cancer more accurately and quickly, and reduce side effects and improve patient quality of life [ 6 , 7 , 9 ].

Chemotherapy is the most commonly used treatment for cancer. Despite advances in cancer treatment in recent years, long-term chemotherapy has led to increased frequency of drug resistance and reduced effectiveness, leading to refractory cancers and cancer recurrence. Analysis of clinical results showed that the emergence of resistance to chemotherapy and targeted therapies has led to a decrease in overall survival (OS) in some cancer patients compared to expectations [ 10 , 11 ]. Thus, alleviating cancer resistance becomes an important goal for cancer treatment. There are two types of resistance to chemotherapy: inherent resistance and acquired resistance. Inherent drug resistance indicates that tumor cells are insensitive to the drug before treatment. Mechanisms for inherent drug resistance include but not limited to presence of cancer stem cells, dysfunction of apoptosis pathway and overexpression of drug efflux transporter [ 10 ]. Acquired drug resistance is a condition in which the originally sensitive tumor develops certain mechanisms after receiving a therapeutic drug and becomes resistant to the drug, such as mutation or change in the expression level of the therapeutic target, activation of alternative signaling pathways and induction of drug efflux transporter after treatment [ 10 ]. At the same time, epigenetic changes and the influence of local tumor microenvironment have been proved to be important factors of chemoresistance [ 12 , 13 ]. Long-term combination of chemotherapy drugs leads to the development of multidrug resistance. Multidrug resistance (MDR) is characterized by cross-resistance of cancer cells to a variety of anti-cancer drugs with different structures and mechanisms of action. Clinical MDR may be caused by many factors including host factors, cancer factors and cancer-host interactions, which are summarized in Fig. 1 . Fig. 1 Factors associated with drug resistance in cancer. Alkylating agents, antimetabolites, topoisomerase inhibitors and mitotic spindle inhibitors are categories of commonly used chemotherapeutic drugs

The control and adaptation of almost all biological processes involve the chemical modification of DNA, RNA and protein synthesis. In recent years, RNA modification has become a hot topic in cancer [ 14 ]. The RNA modification processes are normally regulated by different proteins. Proteins responsible for catalyzing the deposition of specific modifications are termed "writers". The protein components catalyzing the removal of specific modifications are termed "erasers". The family of proteins that identify and bind modified nucleotides are designated as "readers". The proteome of these specific "writers", "erasers" and "readers" is reported to influence the fate of RNA and the expression of cancer-related genes [ 14 , 15 ]. So far, more than 170 different types of RNA modifications have been identified. Some of these modifications are closely related to tumor biological function [ 16 ]. Among them, m 6 A is the most abundant mRNA modification in mammals. It is also found in non-coding RNAs, such as long non-coding RNA (lncRNA), microRNA (miRNA), small nuclear RNA (snRNA) and ribosomal RNA (rRNA) [ 17 – 21 ]. N1-methyladenosine (m 1 A), N6,2'-O-dimethyladenosine (m 6 Am), 5-methylcytosine (m 5 C), 3-methylcytosine (m 3 C), pseudouridine (Ψ), N7-methylguanosine (m 7 G) and ribosomal RNA 2'-O-methylation (2'-O-Me) are also present in mRNA, but so far their influence in cancer is still poorly understood [ 22 ]. Summary of different RNA modifications is presented in Fig. 2 . Fig. 2 Mapping summary of major RNA methylation modifications and their relationship with cancer

Emerging evidence suggest that tRNA modification directly controls translation, thus tRNA modification enzymes can act as regulators of cancer progression. m 1 A modification has been mainly detected in tRNA and rRNA, and modification at tRNA nucleotide position 9 and 58 are the most well studied. The conformational changes induced by these modifications affect the recognition of proteins, which affects biological function [ 23 , 24 ]. Meanwhile, it has been reported that the alteration of m 5 C in eukaryotic tRNA is related to the alteration of protein translation [ 25 , 26 ]. Pseudouridine (Ψ) is another relatively abundant modification found in different RNA species. The existence of Ψ causes the change of RNA conformation, making the short RNA more stable and affecting the efficiency of pre-mRNA splicing [ 27 , 28 ]. Recent study has also identified 5'-cap m 7 G as a type of RNA modification, which can recruit cellular proteins and mediate cap-related biological functions, such as pre-mRNA processing, intracellular substance export, and cap-dependent protein synthesis [ 29 , 30 ]. RNA modifications dynamically regulate RNA metabolism and their dysregulation is closely related to tumor survival, proliferation, self-renewal, differentiation, stress adaptation, invasion and resistance to therapy [ 25 , 26 , 31 ]. Therefore, our understanding of the importance of RNA in cancer has changed.

Role of m 6 A in cancer and drug resistance

m 6 A modification is the methylation of the sixth nitrogen site of RNA adenosine. In 1974, a groundbreaking study first confirmed the presence of m 6 A in mRNAs [ 32 ]. m 6 A is the most abundant methylation modification detected and the most well characterized modification at the functional level in mRNA. Beside mRNA, the biological function of m 6 A in tRNA, rRNA and non-coding RNA has also been gradually discovered by scholars [ 33 ]. N 6 ,2’-O-dimethyladenosine (m 6 Am) is another form of modification presenting in mRNAs and snRNAs [ 34 ]. The modification of m 6 A is dynamic and reversible. Methylation in the 5’UTR region of mRNA plays an important role in mRNA splicing, editing, stability, degradation, polyadenylation, etc., while modification in the 3’UTR region contributes to the nuclear export of mRNA, initiation of translation, and maintenance of mRNA structural stability [ 35 ]. Most m 6 A-modified mRNAs contain only one m 6 A modification site, but some contain 20 or more modification sites [ 36 ]. The regulators of m 6 A RNA methylation, including "writers", "erasers" and "readers", are considered as potential targets for future cancer therapy and current research has also extended to investigation of them in cancer drug resistance [ 37 ] (Fig. 3 & Table 1 ). Fig. 3 Mapping summary of the effect of RNA m 6 A methylation on cancer drug resistance and the function of m 6 A regulator in RNA Table 1 List of effects of m 6 A regulators on drug-resistance of cancer m 6 A regulators Targ ets Expression change Drug resistance Cancer type Drug Ref METTL3 AKT ↑ ↑ AML Cytarabine, Daunorubicin [ 38 ] miR-221-3p ↓ ↓ BC Adriamycin [ 39 ] AK4 ↑ ↑ BC Tamoxifen [ 40 ] PTEN ↓ ↑ CML Adriamycin [ 41 ] TRAF5 ↑ ↑ CRC Oxaliplatin [ 42 ] Sec62 ↑ ↑ CRC Oxaliplatin, 5-fluorouracil [ 43 ] TP53-R273H ↑ ↑ CRC 5-fluorouracil [ 44 ] Circ 0000677, ABCC1 ↑ ↑ CRC 5-fluorouracil, Vincristine [ 45 ] EZH2 ↑ ↑ GBM Temozolomide [ 46 ] MRP1 ↑ ↑ GSC Imatinib [ 47 ] FOXO3 ↑ ↓ LIHC Sorafenib [ 48 ] LINC1273 ↓ ↓ LIHC Sorafenib [ 49 ] LncNIFK-AS1 ↓ ↓ LIHC Sorafenib [ 50 ] EGFR ↑ ↑ Melanoma PLX4032 [ 51 ] TRIM11 ↑ ↑ NPC Cisplatin [ 52 ] miR-4443, FSP1 ↑ ↑ NSCLC Cisplatin [ 53 ] LC3B, ATG5, ATG7 ↑ ↑ NSCLC Gefitinib [ 54 ] Unknown ↓ ↓ PAAD Chemotherapeutic drug [ 55 ] NR5A2 ↑ ↑ PC Enzalutamide [ 56 ] TFAP2C ↑ ↑ Seminoma Cisplatin [ 57 ] PARP1 ↑ ↑ STAD Oxaliplatin [ 58 ] ARHGAP5-AS1 ↑ ↑ STAD Chemotherapeutic drug [ 59 ] METTL3/14 PES1 ↑ ↑ CML Imatinib [ 60 ] CEBPA-DT ↑ ↑ OSCC Cisplatin [ 61 ] TRIM7, BRMS1 ↑ ↑ OS Adriamycin, Methotrexate [ 62 ] METTL3/FTO HSPA7 ↓ ↓ GBM PD1 [ 63 ] METTL3/YTHDF1/3/EIF3B YAP ↓ ↓ NSCLC Cisplatin [ 64 ] METTL3/WTAP c-MET ↓ ↓ NSCLC Crizotinib [ 65 ] METTL3-METTL14-WTAP MAPK13 ↑ ↑ LAM Rapamycin [ 66 ] METTL14 miR-17-5p, MFN2 ↓ ↓ CRC 5-fluorouracil [ 67 ] PRMT3 ↑ ↑ EC Cisplatin [ 68 ] HNF3γ ↓ ↑ LIHC Sorafenib [ 69 ] AC026356.1 ↑ ↑ LUAD Cisplatin [ 70 ] RBM24-AXIN1 ↓ ↑ NSCLC Cisplatin [ 71 ] MN1 ↑ ↑ OS All-trans-retinoic acid [ 72 ] TRAF1 ↑ ↑ RCC Sunitinib [ 73 ] METTL7B GPX4, HMOX1, SOD1 ↑ ↑ LUAD Gefitinib, Osimertinib [ 74 ] METTL7A LOC606724 , SNHG1 ↑ ↑ MM Bortezomib, Melphalan, Carfilzomib [ 75 ] ZCCHC4 AL133467.2 /γH2AX ↓ ↑ LIHC Oxaliplatin [ 76 ] Unknown ↓ SCLC Chemotherapeutic drug [ 77 ] RBMX BLACAT1 ↑ ↑ LIHC Sorafenib [ 78 ] ↓ SCLC Chemotherapeutic drug [ 77 ] WTAP CXCL16/CXCR6 ↑ ↑ OC Cisplatin [ 79 ] TGF-β ↑ ↑ STAD chemotherapy resistance [ 80 ] DUSP6 ↓ ↓ TCL Cisplatin [ 81 ] TNFAIP3 ↑ ↑ Bladder cancer Cisplatin [ 82 ] VIRMA RAB27B ↑ ↑ CML Imatinib [ 83 ] XLF, MRE11 ↑ ↑ GCTs Cisplatin [ 84 ] ↑ LIHC Sorafenib [ 85 ] FOXM1 ↑ ↑ STAD Cisplatin [ 86 ] ALKBH5 JAK2 ↑ ↑ EOC Cisplatin [ 87 ] Circ 0072083 ↓ ↓ GBMLGG Temozolomide [ 88 ] USP1 ↓ ↓ T-ALL Dexamethasone [ 89 ] DDX3 ↑ ↑ OSCC Cisplatin [ 90 ] WIF-1 ↓ ↓ PAAD Gemcitabine [ 91 ] FOXO1 ↑ ↑ TNBC Doxorubicin [ 92 ] ↑ ↑ MM PD-1 [ 93 ] ALKBH5/FTO FZD10, Wnt/β-catenin ↑ ↑ EOC PARP Inhibitor [ 94 ] FTO SOD2 ↑ MM Bortezomib [ 95 ] JPX, PDK1 ↑ ↑ GBM Temozolomide [ 96 ] ABCC10 ↑ ↑ NSCLC Gefitinib [ 97 ] FLRT3, PTGIS, SIRPα ↑ ↑ NSCLC Gefitinib [ 98 ] STAT3 ↑ ↑ BC Adriamycin [ 99 ] ULK1 ↑ ↑ STAD Cisplatin [ 100 ] Unknown ↑ ↑ AML TKI [ 101 ] β-catenin ↑ ↑ LSCC Chemotherapeutic drug [ 102 ] SFP ↓ ↓ CRC 5-fluorouracil, Irinotecan [ 103 ] SIVA1 ↓ ↑ CRC 5-fluorouracil [ 104 ] G6PD, PARP1 ↑ ↑ CRC 5-fluorouracil, cisplatin [ 105 ] LINC01134 ↑ ↑ PAAD Gemcitabine [ 106 ] NEDD4 ↑ ↑ PAAD Gemcitabine [ 107 ] LINC01559 ↑ ↑ BC Docetaxel [ 108 ] YTHDF1 Circ PTK2 ↓ ↓ CRC Oxaliplatin, 5-fluorouracil [ 109 ] GLS1 ↑ ↑ CRC Cisplatin [ 110 ] TREM29 ↑ ↑ OC Cisplatin [ 111 ] SIAH2 ↑ ↑ TNBC Chemotherapeutic drug [ 112 ] NOTCH1 ↑ ↑ HCC Lenvatinib, sorafenib [ 113 ] RPN2 ↑ ↑ Bladder cancer Cisplatin [ 114 ] MHC-I ↓ ↑ MM PD-L1, CTLA-4 [ 115 ] YTHDF2 TUSC7 ↓ ↓ LUAD Erlotinib [ 116 ] Circ ASK1 ↑ ↑ LUAD Gefitinib [ 117 ] ATF3 ↑ ↑ BC 4-hydroxytamoxifen [ 118 ] DAPK3 ↓ ↑ GC Gemcitabine [ 119 ] CDKN1B ↓ ↑ ICC Cisplatin [ 120 ] IGF2BP1 PKM2 ↑ ↓ LIHC 5-fluorouracil [ 121 ] PRMT3, HEG1 ↑ ↑ LIHC Oxaliplatin [ 122 ] cIAP1 ↑ ↑ RMS Chemotherapeutic drug [ 123 ] ERRα ↑ ↑ OS Doxorubicin [ 124 ] IGF2BP2 ERBB2 ↑ ↑ RAIR-PTC TKI [ 125 ] CircITGB6, FGF9 ↑ ↑ OC Cisplatin [ 126 ] ABCB1 ↑ ↑ BC Adriamycin [ 127 ] lncRNA DANCR, PID1 ↑ ↑ GBM Etoposide [ 128 ] ↑ ↑ CRC Chemotherapeutic drug [ 129 ] HMGCS1 ↑ ↑ PC Enzalutamide [ 130 ] IGF2BP3 ABCB1 ↑ ↑ CRC Chemotherapeutic drug [ 131 ] EGFR ↑ ↑ CRC Cetuximab [ 132 ] hCTR1 ↑ ↑ EOC Cisplatin [ 133 ] MIB1 ↑ ↑ GBMLGG Oncolytic virotherapy [ 134 ] COX6B2 ↑ ↑ NSCLC TKI [ 135 ] HNRNPA2B1 miR-222-3p ↑ ↑ BC Fulvestrant , Tamoxifen [ 136 ] miR-29a-3p miR-29b-3p miR-222-3p ↓ ↑ BC Fulvestrant, 4-hydroxytamoxifen [ 137 ] ATG4B ↓ ↑ BC Olaparib [ 138 ] NEAT1 ↑ ↑ GC 5-fluorouracil [ 139 ] FOXM1, LCN2 ↑ ↑ EC Cisplatin [ 140 ] AML acute myeloid leukemia, BC breast cancer, CML chronic myeloid leukemia, CRC colorectal cancer, EC endometrial carcinoma, EOC epithelial ovarian cancer, GBM glioblastoma multiforme, GBMLGG glioma, GC gallbladder cancer, GCTs germ cell tumors, GSC gastrointestinal stromal cancer, LIHC liver hepatocellular carcinoma, LSCC laryngeal squamous cell carcinoma, LUAD lung adenocarcinoma, LAM lymphangioleiomyomatosis, MM multiple myeloma, NPC nasopharyngeal carcinoma, NSCLC non-small cell lung cancer, OC ovarian cancer, OS osteosarcoma, OSCC oral squamous cell carcinoma, PAAD pancreatic cancer, PC prostate cancer, RAIR-PTC radioiodine-refractory papillary thyroid cancer, RCC renal cell carcinoma, RMS Rhabdomyosarcoma , SCLC small cell lung cancer, STAD stomach adenocarcinoma, T-ALL T-cell acute lymphoblastic leukemia, TCL T-cell lymphoma, TNBC triple negative breast cancer

Role of m 6 A writers in cancer and drug resistance

So far, many proteins have been identified to be involved in catalyzing m 6 A formation, such as methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), wilms tumor 1-associating protein (WTAP), Vir like m 6 A methyltransferase associated (VIRMA), RNA binding motif protein 15 (RBM15), RNA binding motif protein 15B (RBM15B), RNA binding motif protein X-linked (RBMX), ZC3H13 (zinc finger CCCH-type containing 13), ZCCHC4 (zinc finger CCHC-type containing 4), methyltransferase-like 5 (METTL5), methyltransferase-like 7A (METTL7A), methyltransferase-like 7B (METTL7B), and methyltransferase-like 16 (METTL16). METTL3 forms a heterodimer complex with METTL14, which synergistically induce m 6 A methylation with the support of other cofactors (WTAP, VIRMA and RBM15/15B) to form the methyltransferase complex (MTC) [ 141 ]. ZCCHC4, as a recently identified methyltransferase, is found to methylate 28S rRNA and can also interact with a small number of mRNA [ 142 ]. The METTL5-TRMT112 (tRNA methyltransferase activator subunit 11–2) complex methylates single m 6 A in the 18S subunit rRNA. TRMT112 can stabilize METTL5 and stimulate the activation of METTL5 to improve its binding ability with SAM [ 143 ]. U6 snRNA is involved in splicing, for which a single m 6 A is catalyzed by METTL16. In addition, METTL16 catalyzes the formation of m 6 A in a few mRNA and non-coding RNA [ 19 ]. The abnormal expression of most of these enzymes is closely related to the occurrence and progression of cancer and cancer drug resistance [ 36 ]. Recently, Chen et al. reported that the expression pattern of writers for four different types of RNA modification including m 6 A may influence the microenvironment of colorectal cancer (CRC) and alter susceptibility to anti-cancer drugs, indicating the cooperation of different types of RNA modification and the importance of RNA modification writers in drug resistance [ 144 ].

METTL3, METTL14 and their heterodimer complex

In 1977, the major regulator in mRNA methylation, METTL3, was successfully cloned [ 145 ]. METTL3 is the only catalytic subunit of the MTC. It is a methyltransferase that use S-adenosylmethionine (SAM) as a methyl donor. It belongs to the common RNA methyltransferases-METTL family which also include METTL1, METTL4, METTL5, METTL14 and METTL16 [ 146 ]. The role of METTL3 in cancer has been extensively studied and well summarized in recent reviews [ 147 , 148 ]. Most studies support an oncogenic role for METLL3, while its effect in several cancer types including glioblastoma and CRC is still controversial [ 149 , 150 ]. In addition, METTL3 has also been demonstrated to contribute to treatment resistance, highlighting the potential of targeting RNA epigenetic mechanisms to conquer cancer drug resistance [ 151 ]. Research by Li et al. revealed the involvement of METTL3 in Temozolomide (TMZ, an alkylating agent that modifies nitrogen atoms as well as epoxy groups on the DNA ring) resistance. TMZ treatment upregulated the expression of METTL3 through SOX4/EZH2, which led to increased m 6 A modification of histone modification-related gene transcripts. Moreover, METTL3 silencing affects EZH2 m6A deposition, which leads to nonsense mediated mRNA decay, and synergized with TMZ to inhibit the growth of TMZ-resistant xenografts. This demonstrated the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ-resistant glioblastoma (GBM) [ 43 ]. Bhattarai et al. showed that METTL3 expression was upregulated in A375R cells and increased the m 6 A modification of EGFR, thereby improving their translational efficiency. It promoted activation of the RAF/MEK/ERK pathway in A375R cells and induced resistance to vemurafenib (an inhibitor of B-Raf V600E ). Conversely, knockdown of METTL3 reduced EGFR expression and restored vemurafenib sensitivity [ 51 ]. Moreover, study by Li et al. showed that METTL3 promoted oxaliplatin (OXA: platinum-based chemotherapeutic drug) resistance in CD133 + STAD stem cells by enhancing PARP1 mRNA stability, thereby increasing base excision repair pathway activity [ 152 ]. It has been found that overexpression of METTL3 mediated m6A modification of the 5’UTR of MRP1 mRNA, binding to YTHDF1 and eEF-1 immediately, promoting MRP1 mRNA translation. And also resulted in imatinib (a tyrosine kinase inhibitor that targets v-Abl, c-Kit, PDGFR, etc.) resistance in gastrointestinal stromal cancers (GIST) patients [ 47 ]. METTL3-mediated m 6 A modification altered the intracellular concentration of imatinib by affecting the expression of multidrug transporter1 (MRP1), thereby regulating the drug resistance of GIST to imatinib. At the same time, study by Zhang et al. revealed that m 6 A modification of tRNA methyltransferase activator subunit 11 (TRIM11) by METTL3 could enhance TRIM11 RNA stability and led to inhibited apoptosis in vitro and promoted cisplatin (DDP: platinum-based chemotherapeutic drug) resistance in vivo in nasopharyngeal carcinoma (NPC) [ 153 ]. Liu et al. showed that METTL3-mediated m 6 A modification upregulated Sec62 expression though stabilizing Sec62 mRNA, which can bind to β-catenin inhibits degradation of β-catenin mRNA and enhance Wnt signaling to promote stemness and chemical resistance of CRC [ 154 ]. All these findings suggest that METTL3 could induce the canonical oncogenic genes or pathways and multidrug resistance genes to promote drug resistance, emphasizing the importance of METTL3 in drug resistance and the feasibility of targeting METTL3 to reverse it.

METTL14 forms stable heterodimers with METTL3 [ 155 ]. Although METTL14 is also a methyltransferase, it acts as an allosteric activator and has no catalytic activity in the MTC. METTL14 stabilizes METTL3, and this dimer jointly mediates the deposition of m 6 A in the nuclear RNA of mammalian cells [ 156 , 157 ]. Like METTL3, both oncogenic and tumor-suppressive roles of METTL14 have been reported [ 158 ], but most studies indicate a tumor-suppressive function for METTL14 [ 158 – 166 ]. At the same time, participation of METTL14 in cancer drug resistance has also been revealed. As reported by Zhou et al. HNF3γ is a hepatocyte nuclear factor and is down-regulated in liver hepatocellular carcinoma (LIHC) patients, which expression of HNF3γ mRNA is mediated through METTL14-dependent m6A. METTL14 promotes degradation of HNF3γ mRNA. Forced expression of HNF3γ sensitized LIHC cells to sorafenib (an inhibitor of Raf, VEGFR, PDGFR, c-Kit and RET) induced growth inhibition and cell apoptosis through OATP1B1 and OATP1B3 trans-activation [ 69 ]. The tumor necrosis factor-related receptor factor TRAF1 was found to regulate renal cell carcinoma drug resistance in a METTL14-dependent manner. Overexpression of TRAF1 inhibits apoptosis while promoting angiogenesis and development of sunitinib resistance [ 73 ]. Sun et al. reported that loss of METTL14 promoted pri-miR-17 mRNA stabilization by inhibiting YTHDC2 recognition and led to CRC progression and 5-fluorouracil (5-FU: an inhibitor of DNA synthesis) drug resistance [ 67 ]. Furthermore, research evidence reveals that dysregulation of METTL3-METTL14 as a dimeric complex affect cancer drug resistance. Ianniello et al. found that the expression of the METTL3-METTL14 complex is associated with TKIs imatinib sensitivity in patients with chronic myeloid leukemia (CML). METTL3/METTL14 is upregulated in CML. Depletion of METTL3 impacts mRNA translation efficiency, while METTL3 directly impacts oncogene PES1 expression. Downregulation of METTL3/METTL14 inhibited the resistance of CML cells to imatinib. They also revealed cytoplasm localization and function of METTL3 independent from its catalytic activity [ 60 ]. From the above results, it’s hard to conclude on the role of METTL14 in cancer drug resistance, thus more studies are needed to further clarify the effect of manipulating METTL14 in drug resistance.

WTAP

WTAP was discovered in a screen for proteins that interact with METTL3 in Arabidopsis thaliana [ 167 ]. WTAP itself has no methyltransferase activity [ 168 ], but it acts as a regulatory subunit of the m 6 A methyltransferase complex and play a key role in the transcriptome regulation of RNA metabolism. There is strong evidence that the RNA-binding capacity of METTL3 is greatly reduced in the absence of WTAP, suggesting that WTAP functions to regulate the recruitment of the m 6 A methyltransferase complex to mRNA targets and is essential for the catalytic activity of m 6 A methyltransferase [ 169 ]. Schöller et al. investigated the interaction between WTAP and the MTTL3/14 complex and found that WTAP and the dimer complex are transported to the nucleus independently and bind each other in the nucleus. Moreover, WTAP targets METTL3 to specific sites such as nuclear speckles [ 170 ]. Interestingly, recent reports have demonstrated that WTAP also affects the development of cancer and the sensitivity of drug-resistant cells. Ma et al. reported that WTAP promoted cell proliferation and cisplatin resistance in nasal-type natural killer/T-cell lymphoma (NKTCL) by increasing the stability of dual-specificity phosphatase 6 (DUSP6) Mrna through m 6 A RNA methylation [ 81 ]. Huang et al. found that overexpression of lncRNA DLGAP1-AS1, which is induced by WTAP, enhanced Adriamycin (an inhibitor of DNA topoisomerase I and II) resistance in BC cells through micro RNA miR-299-3p [ 171 ]. Research evidence also demonstrated that circular RNA circ0008399 can bind WTAP and promote the formation of the METTL3/METTL14/WTAP methyltransferase complex. Circ0008399 increased mRNA stability of TNF alpha-induced protein 3 (TNFAIP3) through m6A-dependent, thereby increasing its expression. Mechanistically, activation of the circ0008399/WTAP/TNFAIP3 pathway reduces the chemosensitivity of bladder cancer to DDP, suggesting that targeting of this pathway might be promising in sensitizing bladder cancer to DDP chemotherapy [ 82 ]. Study by Ding et al. found that co-treatment of chidamide (an inhibitor of HDAC1, 2, 3, 10) with crizotinib (an inhibitor of c-Met , ALK, ROS1) could overcome crizotinib resistance in non-small cell lung cancer (NSCLC) by decreasing c-MET expression and inhibiting the activity of c-MET downstream molecules, which is through downregulation of METTL3 and WTAP, then inhibits translation of c-MET mRNA [ 65 ]. Most studies suggest that WTAP contributes to drug resistance and targeting WTAP could reverse the resistance.

VIRMA

Another important member of the methyltransferase complex is KIAA1429 and was later known as VIRMA (Vir-like m 6 A methyltransferase). VIRMA is a macromolecular protein with a molecular weight of 202 kDa and is currently the largest component of the m 6 A methyltransferase complex. VIRMA guides methyltransferase components to specific RNA regions [ 172 , 173 ] and Schwartz et al. demonstrated that VIRMA is required for full methylation program because knockdown VIRMA resulted in more prominent decrease in m 6 A level than knockdown of either METTL3 or METTL14 [ 174 ]. It has been demonstrated that VIRMA mediates preferential methylation of mRNA in 3’UTR and near stop codons [ 175 ]. The expression of VIRMA has been associated with cell cycle progression, migration, invasion, cancer apoptosis and progression in multiple malignancies [ 173 ]. The team of Miranda-Gonçalves et al. found that knockdown of VIRMA resulted in disruption of the remaining methyltransferase complex and reduced m 6 A abundance. In vivo and in vitro study confirmed that knockdown of VIRMA also reduced the aggressiveness of germ cell cancer (GCT) cells and increased sensitivity to cisplatin therapy by increasing DNA damage (enhanced γH2AX, GADD45B mRNA transcription) and downregulate the translation of XLF and MRE11 mRNA [ 84 ]. It has also been shown that VRIMA expression was increased in sorafenib-resistant HCC cells and tissues and silencing VIRMA inhibited vascular formation induced by sorafenib-resistant cell culturing medium [ 87 ].

METTL7A and METTL7B

Both methyltransferase-like protein 7A (METTL7A) and METTL7B belong to the methyltransferase-like protein (METTL) family, whose members are characterized by an S-adenosylmethionine (SAM) structural domain. They are potential m 6 A methyltransferases as suggested by recent research evidence. Studies have shown that METTL7A affects genes related to osteogenic differentiation, which in turn affects stem cell survival and osteogenic differentiation [ 176 , 177 ]. For the first time, [ 63 ] demonstrated that METTL7A has RNA methyltransferase activity and participates in the methylation of lncRNA m 6 A modification and promotes adipocyte induced multiple myeloma (MM) resistance [ 75 ].

METTL7B encodes a protein that can methylate small molecules alkyl mercaptan and participate in hydrogen sulfide metabolism [ 178 ]. Ignatova et al. revealed that METTL7B interacts with mitochondrial proteins, suggesting that METTL7B may have a potential function in RNA methylation [ 179 ]. Meanwhile, studies have shown that METTL7B is up-regulated in most cancers [ 180 ]. Song et al. found that global m 6 A levels were elevated in METTL7B-overexpressed LUAD cells, and was reduced by METTL7B knockdown. They also demonstrated that the expression of METTL7B was increased in TKI resistant LUAD cells. METTL7B increased the transcription of GPX4, HMOX1, and SOD1 mRNA. It was also found by in vitro and in vivo study that METTL7B knock-down re-sensitizes LUAD cells to gefitinib (an EGFR-TKI) and axitinib (an inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, c-Kit), suggesting METTL7B inhibitors might be useful in reversing TKIs resistance in LUAD patients [ 74 ].

Role of m 6 A erasers in cancer and drug resistance

The primary function of the m 6 A “erasers” is to reverse the methylation of m 6 A. “Erasers” first oxidize m 6 A to N6 hydroxymethyl adenosine (hm 6 A), followed by conversion to N6 formyl adenosine (f6A), and finally to form adenosine (A), ending the demethylation process. Fat mass and obesity-associated protein (FTO) and ALKB homolog 5 (ALKBH5) have been identified as m 6 A demethyltransferases, and are closely related to the progression of LIHC, pancreatic adenocarcinoma (PAAD), BC, CRC and other types of cancer [ 181 , 182 ].

FTO

FTO, originally identified as a key protein associated with obesity, was the first defined m 6 A demethylase and also demethylates m 6 Am. In 2011, a study demonstrated that FTO localizes in nuclear speckles and can eliminate the m 6 A residues in RNA and also acts on m 6 Am on the 5’ cap of mRNA and snRNA [ 183 ]. The confirmation of FTO as a m 6 A "eraser" has accelerated study of it in cancer and drug resistance [ 181 , 184 ]. Most of the studies reveal a tumor-promoting role for FTO [ 185 ], whereas there are also rare reports of its tumor-suppressive function [ 186 , 187 ]. As for the role of FTO in drug resistance, Wang et al. demonstrated that FTO affected the destabilization of SOD2 mRNA in multiple myeloma dependent of m 6 A modification, thereby promoting bortezomib (an inhibitor of NF-κB) resistance [ 95 ]. Study has also shown that inhibition of FTO could reverse 5-FU-resistance through FTO-SIVA1 axis in CRC. However, SIVA1 at CDS regions induces its mRNA degradation via FTO-YTHDF2-dependent mechanism. [ 104 ]. Also in CRC, it has been found that FTO contributed to chemotherapy resistance via regulating G6PD/PARP1 mRNA stability and knockdown of FTO sensitized CRC cells to 5‐FU and cisplatin [ 105 ]. Li et al. showed that lncRNA just proximal to the X-inactive specific transcript (JPX), interacted with FTO in glioblastoma multiforme cells and enhanced FTO-mediated phosphoinositide dependent kinase-1 (PDK1) mRNA demethylation, which promoted aerobic glycolysis and TMZ chemoresistance in an m 6 A-dependent manner [ 96 ]. Study by Sun et al. demonstrated that SaikosaponinD (SSD) targets FTO directly, thus increasing global m 6 A RNA methylation and reducing the stability of downstream gene transcripts. SSD can also overcome resistance to TKI [ 101 ]. Gefitinib is suitable for the treatment of locally advanced or metastatic NSCLC, but its drug resistance limits the long-term treatment of patients [ 188 ]. Xiao et al. confirmed that gefitinib-resistant cell derived exosomes increased ABCC10 mRNA translation of recipient cells in a FTO-dependent manner and FTO reduction in donor exosomes decreased the acquired resistance of recipient cells. This resistance mechanism is through the FTO/YTHDF2/ABCC10 axis [ 97 ]. Also, reducing FTO increased PTEN mRNA translation capacity in a NEDD4-dependent manner, and affected the chemosensitivity of pancreatic cancer cells to gemcitabine through the PI3K/AKT pathway [ 107 ]. It can be inferred from these studies that targeting FTO might be a promising way to reverse drug resistance.

ALKBH5

ALKBH5, a member of the ALKBH family, is another mammalian demethylase. As the second defined m 6 A demethylase, ALKBH5 significantly influences RNA metabolism and mRNA export, as well as assembly of mRNA processing factors in nuclear spots by reducing m 6 A levels [ 189 ]. Oncogenic function of ALKBH5 has been widely reported. It can promote cancer proliferation, metastasis, stemness and drug resistance and also influence tumor immune infiltration and metabolism [ 190 ]. However, the number of investigations on the involvement of ALKBH5 in drug resistance is relatively small. Nie and their group have found that overexpression of ALKBH5-HOXA10 loop promotes cisplatin resistance in epithelial ovarian cancer (EOC) by co-activating JAK2/STAT3 signaling pathway via JAK2 m 6 A demethylation. ALKBH5 erases m6A modifications of JAK2 mRNA and maintains JAK2 mRNA expression by lowering YTHDF2-mediated mRNA degradation. Therefore, inhibition of the JAK2/STAT3 signaling pathway or knockdown ALKBH5 and HOXA10 in EOC cells can sensitize EOC cells to cisplatin [ 87 ]. Recently, scholars observed elevated circ 0072083 expression in TMZ-resistant glioma tissues and cells and increased exosome circ 0072083 in TMZ-resistant patients. Silencing circ 0072083 inhibited ALKBH5-mediated demethylation to reduce Nanog homeobox (NANOG) expression, which was through targeting miR-1252-5p and also inhibit TMZ resistance in glioma patients [ 88 ]. Study by Gong et al. reported that downregulation of ALKBH5 lowers ubiquitin-specific protease1 (USP1) and AuroraB mRNA translation, and promotes the sensitivity of CEM-C1 cells to dexamethasone (a modulator of interleukin receptor) [ 89 ]. It has recently been shown that ALKBH5 promoted the stability of FOXO1 mRNA and found superoxide dismutase (SOD2) overexpression in doxorubicin (DOX)-resistant triple negative breast cancer (TNBC) cells. Increasing expression levels of ALKBH5, FOXO1, and SOD2 are significantly positively associated with chemoresistance and poor prognosis in TNBC patients, and it contributed to maintaining cancer stem cells (CSCs) characteristics in TNBC [ 92 ]. Importantly, ALKBH5 mutation and expression status was correlated with response to immunotherapy in melanoma patients and inhibiting ALKBH5 enhanced the efficacy of anti-PD-1 therapy [ 93 ]. The above findings indicate that ALKBH5 contributes to cancer drug resistance and inhibiting ALKBH5 could sensitize tumor cells to chemotherapy and check point inhibitors.

Role of m 6 A readers in cancer and drug resistance

m 6 A readers mainly consist of four classes of proteins, including the YT521-B homology domain family (YTHDF), the heterogeneous nuclear ribonucleoproteins (HNRNPs) family, the insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) family and eukaryotic initiation factor 3 (eIF3). Some new m 6 A “readers” were subsequently identified, such as PRRC2A (proline-rich and coiled-coil-containing protein 2A) [ 191 ], FMRP (the fragile X mental retardation protein) [ 192 ] and RBM33 (RNA binding motif protein 33) [ 193 ]. These proteins recognize and bind m 6 A-modified transcripts and regulate various biologic processes such as mRNA stability, mRNA splicing, mRNA structural formula, messenger ribonucleic acid export, translational efficiency, miRNA biogenesis and gene expression [ 184 ].

YTHDF family

YTHDF1/2/3 of the YTHDF family function as cytoplasmic m 6 A readers [ 194 ]. Among them, YTHDF1 affects translation by interacting with translation initiators and ribosomes. YTHDF2 reduces mRNA stability by recruiting RNA decay machinery factors [ 195 ]. YTHDF3 synergizes with YTHDF1 to promote protein synthesis and regulate the decay of m 6 A modified mRNA mediated by YTHDF2 [ 196 ]. Most studies concordantly agree that all three YTHDF members paly oncogenic roles in different cancers [ 197 ]. The relationship between these members and drug resistance has also been extensively studied in recent years. Study by Wu et al. found that YTHDF1 was upregulated in TNBC and knockdown of it promoted chemosensitivity through inhibiting the translation of SIAH2 mRNA and downregulating the Hippo pathway [ 198 ]. Recent study also shows that YTHDF1 was highly expressed in HCC and liver CSC and YTHDF1 binds to m6A-modified NOTCH1 mRNA and enhances its stability and translational ability. It promoted resistance to lenvatinib (an inhibitor of VEGF, FGFR1-4, PDGFR, c-Kit, c-RET) and sorafenib in patient-derived organoids. Moreover, lipid nanoparticles targeting YTHDF1 re-sensitized tumor to lenvatinib and sorafenib in vivo [ 113 ]. Importantly, YTHDF1 expression was inversely correlated with immune infiltration and anti-PD-1 response in melanoma. Knockout of YTHDF1 synergized with anti-PD-L1 or anti-CTLA-4 antibody to exert antitumor activity and prevented tumor relapse in vivo . Mechanistically, reducing YTHDF1 inhibits translation of lysosomal genes and limits major histocompatibility complex class I (MHC-I) and lysosomal proteolysis of antigens [ 115 ]. It has been reported that the combination of cisplatin with glutamine metabolism inhibitors may be an effective method to improve the drug resistance and side effects of chemotherapy. Chen's team found that YTHDF1 was increased in cisplatin resistant CRC cells and overexpression of it leads to cisplatin resistance by promoting protein synthesis of glutaminase 1 (GLS1). Blocking YTHDF1 mediated GLS1 and glutamine metabolism re-sensitized drug-resistant CRC cells to cisplatin [ 110 ]. These results suggest that inhibition of YTHDF1 could sensitize tumor to both chemotherapy and immune checkpoint inhibitors (ICI).

Meanwhile, Li et al. showed that YTHDF2 can inhibit the translation of TUSC7 mRNA, which contribute to drug resistance. TUSC7 formed feedback loop with miR-146a/Notch signaling, which in turn sensitized erlotinib (an inhibitor of EGFR) resistant PC9 cells (PC9ER) and HCC827 cells [ 116 ]. Study by Wang et al. reported that YTHDF2-mediated m 6 A-modified circASK1-encoded a novel protein to improve the resistance of LUAD to gefitinib by competitively activating ASK1-dependent apoptosis [ 117 ]. Moreover, YTHDF2 promotes cyclin dependent kinase inhibitor 1B (CDKN1B) mRNA degradation by an m6A-dependent manner, and also enhancing DNA damage. Downregulation of CDKN1B increased the effect of YTHDF2 silencing on tumorigenesis and cisplatin response to intrahepatic cholangiocarcinoma (ICC) and chemoresistant tissues. Knockdown of YTHDF2 led to sensitization to cisplatin treatment both in vitro and in vivo [ 120 ]. From Zhao's study, YTHDF3 was found to be highly expressed in oxaliplatin resistant CRC tissues and cells. It could recognize the 5’UTR region of m 6 A-methylated RNAs associated with cancer resistance and recruited eukaryotic translation initiation factor 3 subunit A (eIF3A) to promote translation of target genes [ 199 ]. Benavides-Serrato et al. showed that YTHDF3 bound to m 6 A-modified cyclin D1 and c-MYC IRES, altered IRES activity and regulated the sensitivity of glioma cells to mTOR inhibitors in vivo and in vitro [ 200 ]. However, direct evidence of the effect of manipulating YTHDF3 on drug resistance is lacking.

IGF2BP family

The IGF2BPs (IGF2BP1/2/3) are a conserved family of oncofetal RNA-binding proteins that control the localization, translation and stability of m 6 A-modified mRNAs [201same m 6 A site to co-regulate mRNA expression [ 201 ]. Recent studies have shown that IGF2BPs preferentially recognize m 6 A modified mRNAs and promote the stability and translation of thousands of potential mRNA targets in an m 6 A dependent manner. IGF2BPs and YTHDF2 have opposite effects on mRNA, which is not well understood and brings additional complexity to the function of m 6 A. IGF2BPs and YTHDF2 may recognize different sites, or compete for the same m 6 A site to co-regulate mRNA expression [ 33 , 202 ]. IGF2BPs play carcinogenic roles in cancer by stabilizing the methylated mRNAs of oncogenic targets like MYC [ 202 , 203 ]. In Rhabdomyosarcoma (RMS), IGF2BP1 drove translation of the cellular inhibitor of apoptosis 1 (cIAP1) and knocking down IGF2BP1 or using IAP antagonists sensitized cells to TNF-α-mediated cell death [ 123 ]. In osteosarcoma (OS), IGF2BP1 stabilized ERRα mRNA to influence metabolic reprogramming, which contributed to the chemoresistance of OS cells [ 124 ]. Moreover, it has been found that PRMT3 was a key driver of oxaliplatin resistance in HCC dependent on the methylation of IGF2BP1, which stabilized HEG1 mRNA [ 122 ].

For IGF2BP2, Sa et al. have shown that IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to TKIs in the differentiation therapy of radioactive iodine-refractory papillary thyroid carcinoma [ 125 ]. Study has also shown that circITGB6 induced cisplatin resistance by interacting with IGF2BP2 to stabilize FGF9 mRNA [ 126 ]. IGF2BP2 and DANCR were highly expressed in glioma cells and tissues, while PID1 and FOXO1 were less expressed. Overexpression of IGF2BP2 promotes stability of DANCR mRNA, which interacts with FOXO1, which promotes transcriptional expression of PID1, thereby enhancing sensitivity of GBM cells to etoposide (an inhibitor of topoisomerase II) [ 128 ]. In addition, IGF2BP2 expression was associated with resistance to selumetinib (an inhibitor of MEK1/2), gefitinib, and regorafenib (an inhibitor of VEGF, PDGFR-β, c-Kit, c-RET, Raf-1) in patient-derived organoids (PDOs) and to 5-fluorouracil and oxaliplatin in patient-derived xenografts (PDXs) in vivo in CRC. Knockout of IGF2BP2 translation efficiency of respiratory chain complex I, complex IV, and mitochondrial outer membrane-associated genes was reduced, allowing resistant cells to return to sensitivity [ 129 ].

Increased expression of IGF2BP3 has been associated with higher risk of developing chemoresistance in epithelial ovarian carcinoma (EOC) patients [ 133 ]. Moreover, IGF2BP3 promoted resistance to both EGFR-TKIs [ 135 ] and EGFR-targeted antibody cetuximab [ 132 ] in NSCLC and CRC respectively. A recent study proved that upregulation of IGF2BP3 enhances translation of the E3 ubiquitin protein ligase MIB1 mRNA and promotes degradation of FTO via the ubiquitin proteasome pathway. And targeting IGF2BP3-induced NETosis could even overcome resistance in oncolytic virotherapy in glioma [ 134 ]. IGF2BP1/2/3 are crucial mediators for resistance to different therapies, including chemotherapy, targeted therapy, immunotherapy and oncolytic virotherapy.

HNRNPA2B1

HNRNPA2B1 belongs to the heterogeneous nuclear ribonucleoparticles (HNRNP) family, in addition to A1, A3 and A0, which are all involved in many important cellular activities through transcriptional regulation [ 204 ]. With the deepening of m 6 A modification research, HNRNPA2B1 has been identified as a nuclear m 6 A "reader", which induces alternative splicing effects similar to METTL3 and also regulates primary miRNA processing [ 205 , 206 ]. Methylation of purines may lead to changed secondary structure of RNAs, which may alter their interactions with "readers" proteins in turn. This structure allows HNRNPA2B1 to interact with mRNA to affect cancer progression [ 206 – 208 ]. According to the literature, HNRNPA2B1 mainly exerts a tumor-promoting effect [ 209 ] and is also an important player in drug resistance. Petri et al. demonstrated that HNRNPA2B1 were upregulated in tamoxifen (TAM: an antiestrogen) resistant ERα BC cells and BC tumors. Overexpressing HNRNPA2B1 in MCF-7 cells resulted in drug resistance to TAM and fulvestrant (an antagonist of estrogen receptor). Meanwhile, knockdown of HNRNPA2B1 in LCC9 and LY2 cells restored TAM and fulvestrant, endocrine-sensitivity [ 136 ]. Recent study by Wang et al. reported that HNRNPA2B1 was highly expressed in patient samples of non-responders to chemotherapy and inhibition of HNRNPA2B1 sensitized GC cells to chemotherapy [ 139 ]. It has been reported that HNRNPA2B1 binds to the 3’UTR of FOXM1 and stabilizes FOXM1 mRNA through m6A modification. FOXM1 positively regulates LCN2 expression in EC cells by binding to the LCN2 promoter. Knockdown of FOXM1 downregulates DDP-resistant endometrial cancer (EC) cells [ 140 ]. Thus, targeting HNRNPA2B1 seems feasible in reversing cancer drug resistance.

Role of m 5 C in cancer and drug resistance

m 5 C is widespread in RNA and most abundant in eukaryotic tRNA and rRNA [ 210 ]. Using improved Bisulfite sequencing and new computational methods, hundreds of m 5 C sites in the mammalian transcriptome have been detected [ 211 ]. However, the exact mechanism of m 5 C in mRNA deposition and molecular function are still not fully explored [ 26 ]. Nonetheless, "writers" and “readers” of m 5 C have been confirmed to regulate gene expression level post-transcriptionally and participate in cellular activities [ 212 ]. So far, the m 5 C "writers" include NSUN1-7 and DNMT2. Originally identified to catalyze 5-methylcytosine in DNA, DNMT2 has been found to mediate RNA m 5 C only in recent years [ 213 ]. It was first found to catalyze m 5 C in tRNA and later in mRNA. According to the literature, m 5 C "writers" have been proved to be related to many human cancers [ 210 ], including LIHC, TNBC, STAD, lung squamous-cell carcinoma (LUSC), GBM, CRC and Ewing sarcoma [ 214 – 220 ]. It has been reported that overexpression of NSUN1 could increase the proliferation and malignant transformation of mouse fibroblasts in vitro and promote tumor growth in vivo [ 221 ]. Janin et al. reported that NSUN5 was transcriptionally silenced by DNA methylation and loss of NSUN5-mediated methylation modification in rRNA enabled the ribosome to adapt to specific translation of stress-related mRNA and restrained the ribosome's translational capacity [ 222 ] . Interestingly, epigenetic inactivation of NSUN5 was predictive of long-term survival in glioma patients [ 222 ].

So far, the DNA dioxygenases ten-eleven translocations (TETs), including TET1-3, are believed to also function as "erasers" of m 5 C. As reported, m 5 C can be oxidized to 5-hydroxymethylcytidine (5-hmC) by enzymes of the TETs family in mRNA, thereby affecting a series of biological functions [ 223 , 224 ]. Moreover, TET2 has also been shown to regulate RNA stability via m 5 C modification in RNA [ 225 ]. The involvement of TETs in cancer has been reported. One study suggested that circTRIM33-12 regulated TET1 expression to affect LIHC cell proliferation, migration, invasion and immune evasion [ 226 ]. At the same time, downregulation of TET2 promoted PC and BC [ 227 , 228 ] and lncRNA MIR22HG regulated TET3 to inhibit proliferation of osteosarcoma cells [ 229 ].

Recently, ALYREF and YBX1 were identified as m 5 C "readers" and their involvement in cancer has also been reported [ 26 ]. Wang et al. report that overexpression of ALYREF promotes bladder cancer cell proliferation through PKM2-mediated glycolysis [ 230 ]. Besides, other studies have confirmed that high expression of ALYREF promoted the progression of LIHC and oral squamous cell carcinoma(OSCC) [ 231 , 232 ]. It has been demonstrated that the survival rate of bladder cancer patients was poor in the case of high expression of NUSN2, Y-box binding protein 1 (YBX1) and heparin binding growth factor (HDGF) at the same time [ 233 ].

In recent years, the role of m 5 C in drug resistance has gradually been reported. Cheng et al. demonstrated that NSUN3 and DNMT2 could directly bind to a conserved RNA-binding protein HNRNPK to generate 5-azacitidine (5-AZA: an inhibitor of DNA methyltransferase)-sensitive chromatin structure, but NSUN1 binds BRD4 and RNA-polymerase-II to form a 5-AZA insensitive chromatin structure. In addition, 5-AZA-resistant leukemia cells have increased m 5 C and NSUN1-/BRD4-associated active chromatin [ 234 ]. Okamoto's team showed that knocking down NSUN2 and METTL1, which are phosphorylated by Aurora-B and AKT, respectively, significantly increased the sensitivity of HeLa cells to 5-FU through inhibiting tRNA modification [ 235 ]. Study by Gao et al. showed that YBX-1 was ubiquitinated by SIAH1 at lys304, resulting in the destabilization of its target m 5 C-modified mRNA, thereby sensitizing EOC cells to cisplatin. Therefore, the SIAH1/YBX-1 interaction can be deemed as a potential target for overcoming EOC chemoresistance [ 236 ]. Although the exact functional influence of m 5 C has not been extensively studied, research evidence suggests that m 5 C regulators might also play important roles in cancer and drug resistance.

Role of m 1 A in cancer

In 1961, N1-methyladenosine (m 1 A) was discovered in RNA [ 237 ]. After that, the existence of m 1 A post-transcriptional modification was found in tRNA, rRNA, non-coding RNA and mRNA [ 23 , 238 , 239 ]. m 1 A plays an important role in regulating gene expression and controlling cell survival [ 239 ], thereby affecting the occurrence and progression of diseases [ 240 , 241 ]. The identified m 1 A "writers" include tRNA methyltransferase activator subunit (TRMT) 61A, 61B, 10C and 6 [ 242 ]. m 1 A modification can occur at positions 9、14、22、57 and 58 of human tRNA [ 23 ]. The modification at site 9 is catalyzed by TRMT10C [ 243 ] and modification of site 58 can be catalyzed by TRMT6, TRMT61A and TRMT61B [ 244 ]. Macari et al. found that TRMT6 and TRMT61 were involved in the translation of a group of mRNAs which encoded proteins associated with tumorigenesis and that high expression of TRMT6 and TRMT61 promoted GBM development [ 245 ] vivo through PI3K/AKT pathway ]. TRMT6 was found overexpressed in HCC tissues and promoted HCC in vitro and in vivo through PI3K/AKT pathway [ 246 ]. At the same time, higher expression of TRMT6 was shown to be associated with reduced overall survival (OS) and relapse-free survival (RFS) in patients with primary HCC [ 247 ]. It has also been reported that TRMT6 promoted glioma progression by regulating cell cycle, PI3K-AKT, TGF-beta and other signaling pathways [ 248 ]. Recently it is revealed that silencing TRMT6/TRMT61A reduced proliferation in bladder cancer and they might contribute to cellular stress tolerance [ 249 ]. All the evidence points to a carcinogenic role for TRMT6.

According to the literature, ALKBH1 and ALKBH3 can be regarded as m 1 A "erasers" and remove m 1 A by oxidative demethylation [ 242 , 250 ]. Interestingly, proteins such as YTHDF1, YTHDF2, YTHDF3, and YTHDC1, which contain YTH domains, are deemed as m 1 A “readers” which bind directly to m 1 A-bearing RNAs, similar to m 6 A [ 251 ]. ALKBH1 has recently been demonstrated to promote cancer progression in various cancers [ 252 – 254 ]. Similarly, ALKBH3 has also been found to contribute to cancer survival, invasion and angiogenesis, etc. [ 255 – 257 ]. In contrast, Esteve-Puig et al. found that epigenetic inactivation of ALKBH3 blocks downstream m 1 A RNA demethylation and promotes Hodgkin lymphoma progression [ 258 ]. At the same time, low expression of ALKBH1 is related to poor prognosis of PAAD patients [ 259 ]. Notably, scientists have tried to screen and optimize ALKBH3 inhibitors by preliminary studies [ 260 – 262 ] and one recent study has reported a selective ALKBH1 inhibitor [ 263 ]. Nonetheless, discovery for small molecule inhibitors of these two enzymes is overall not successful.

Role of m 3 C in cancer

m 3 C modification is the methylation of RNA cytosine at position 3 to give m 3 C. METTL2 and METTL6 are members of the methyltransferase-like protein family and catalyze the formation of m 3 C in specific tRNAs in mammals. METTL2-modified m 3 C is located at position 32 of the tRNAThr allelic receptor and tRNAArg (CCU) and METTL6 catalyzes the formation of m 3 C at C32 of specific serine tRNA isoacceptors [ 264 ]. METTL8, another “writer” of m 3 C, catalyzes the formation of m 3 C methylation only in mRNA. Up to now, study on the role of METTL2, METTL6 and METTL8 in cancer is very limited. Ignatova et al. has shown that knocking down METTL6 inhibited tumor cell growth, affected pluripotency and decreased metabolic activity in mice [ 264 ]. In accordance, knocking out METTL6 also decreased cell viability, migration and invasion in HCC via regulating cell adhesion‑related genes [ 265 ]. METTL8 has been shown to influence the formation of regulatory triple-stranded DNA-DNA: RNA hybrid structures (R loops) to promote tumorigenesis [ 266 ]. In BC, METTL8 is regulated by the Yin Yang 1 (YY1) transcription factor and promotes cancer cell migration by affecting ARID1A expression [ 267 ]. METTL8 has also been found to be overexpressed in lung squamous cell carcinoma (LSCC) and negatively correlated with CD8 + T cells infiltration. Inhibition of METTL8 suppressed cancer progression in vitro and in vivo [ 268 ]. Wang et al. analyzed the expression level of genes related to m 3 C and discovered that METTL2A had a high amplification frequency in breast invasive carcinoma (BRCA) and is indicative of poor overall survival (OS) [ 269 ]. As for m 3 C “erasers”, it was found that overexpression or knockdown of ALKBH1 in LIHC cells induced decreased and increased m 3 C levels in mRNA, which suggests that ALKBH1 functions as a m 3 C “eraser” [ 270 ]. ALKBH3 also catalyzes the demethylation of m 3 C in tRNA [ 271 ].

Role of m 7 G in cancer and drug resistance

m 7 G is a modified guanosine that usually locates inside the 5'-cap of mRNA [ 272 ], or present inside rRNA and tRNA [ 273 – 275 ]. Recently, it has also been found in microRNA [ 276 ]. In mammals, the most extensively studied m 7 G regulatory factor is METTL1, which binds to WD repeat domain 4 (WDR4) to form a complex. METTL1-WDR4 acts as methylate transferase of m 7 G and is also homologue of the transfer RNA methyltransferase 8p (Trm8p) / Trm82p heterodimer complex in yeast [ 275 ]. To date, a large number of studies have demonstrated that METTL1-WDR4 complex affects target gene expression and regulates tumor-related biological functions by regulating m 7 G modification levels. Research evidence have shown that METTL1 or WDR4 is significantly up-regulated in AML, bladder cancer, esophageal squamous cell carcinoma (ESCC), LIHC, head and neck squamous cell carcinoma (HNSCC), intrahepatic cholangiocarcinoma (ICC), LUAD, NPC to promote cancer cell proliferation and accelerate cancer progression [ 30 ] (Fig. 4 ). Fig. 4 Summary of the regulatory role of m 7 G in cancer

m 7 G modification has also been implicated in cancer treatment resistance. One study showed that the eIF4F eukaryotic translation initiation complex can bind to the 5'-end mRNA m 7 G cap and persistent formation of this complex was associated with anti-BRAF and/or anti-MEK resistance in BRAF (V600) mutant tumor. Inhibiting the eIF4F complex or targeting eIF4A, synergizes with inhibiting V600 to kill cancer cells [ 277 ]. Lenvatinib belongs to tyrosine kinase inhibitors that is the first-line treatment for advanced LIHC. Huang's team demonstrated that m 7 G methyltransferase complex METTL1-WDR4 was upregulated in lenvatinib-resistant cells and METTL1 regulated the translation of EGFR pathway genes to trigger drug resistance. Overexpression of METTL1-WDR4 promoted the proliferation ability of LIHC cells and enhanced lenvatinib resistance [ 278 ]. According to study by Chen et al., METTL1 and WDR4 were upregulated in NPC. METTL1 induced WNT/β-catenin signaling pathway and EMT and promoted resistance to cisplatin and docetaxel ( a depolymerization inhibitor of microtubules). Conversely, overexpression of WNT3A inhibited METTL1 induced chemoresistance. Moreover, depletion of METTL1 decreased m 7 G tRNA modification and expression, thus decreasing the translation efficiencies of mRNAs with high m 7 G codons [ 279 ]. These studies provide direct evidence that m 7 G modification is involved in promoting drug resistance.

Role of pseudouridine (Ψ) in cancer

Ψ is formed by the ligation of uracil and the fifth position of ribose to form C–C pyrimidine nucleosides, rather than the usual C1-N1 bond. Pseudouridine is the most abundant post-transcriptional modification to RNA, it is found on tRNA, rRNA, snRNA, snoRNA, lncRNA, mRNA. Currently, the main research direction of Ψ is in non-coding RNA [ 280 , 281 ]. Although it is the first nucleoside modification discovered, investigation of it is only beginning in recent years. In mRNA, Ψ-modified mRNAs are translated more slowly compared to unmodified mRNAs [ 282 ]. In addition, mRNAs containing Ψ modifications exhibit greater stability in specific mammals or cells [ 283 – 285 ]. In tRNA, the presence of Ψ stabilizes its tertiary structure and plays an important role in base pairing of codons with anticodons [ 286 ]. Unlike other modifications, pseudouridine is not formed catalyzed by methyltransferases enzymes. There are two major ways of pseudouridylation: RNA-independent way, catalyzed by pseudouridine synthases (PUSs), and RNA-dependent mechanism. In the RNA-independent manner, the PUS family, consisting of ten different members named PUS1-PUS10, directly recognize and catalyze the conversion. Recently the catalytic mechanism of PUS enzymes has been described as U in tritiated substrates, then passed covalent compounds resulting from deprotonation of C2' allowing them to racemize and reattach to C5 of the pyrimidine ring, which in turn forms Ψ [ 287 ]. The nucleolus-associated protein dyskeratosis congenita 1(DKC1), another “writer” of Ψ, catalyzes the RNA-dependent conversion by forming a complex with the guide RNA and other core proteins including NOP10, NHP2, and GAR1 [ 288 , 289 ]. Until now, no enzyme has been defined as Ψ “eraser” or “reader” [ 289 ] and Ψ is believed to be an irreversible process.

The involvement of Ψ in tumorigenesis has gradually been revealed in recent years. By genome-wide RNAi screening, DKC1 was found to be a key regulator in CRC. DKC1 bound to and stabilized several ribosomal proteins. Knockdown of DKC1 or addition of its inhibitor pyrazolofurazine could inhibit the proliferation of CRC cells [ 290 ]. Another study demonstrated that SNORA70E, a small nucleolar non-coding RNA (snoRNA), catalyzed Ψ modification by binding with DKC1 to increase RAS-associated protein 1B (RAP1B) protein level in ovarian cancer (OC). Silencing of DKC1/RAP1B in SNORA70E overexpression cell suppressed cell proliferation, migration, and invasion by decreasing β-catenin, PI3K, AKT1, mTOR, and MMP9 [ 291 ]. Meanwhile, PUS1 and DKC1 were shown to be candidate biomarkers predicting poor prognosis in BC patients and recognized as promising targets for the treatment of BC [ 292 , 293 ]. Cui et al. found that PUS7 was highly expressed in GBM, which was associated with worse survival in GBM patients and PUS7 was required for GSC tumorigenesis. They screened small molecule inhibitor C17 of PUS7, which inhibited GSC growth by inhibiting PUS7-mediated Ψ modification in a dose-dependent manner and also suppressed tumorigenesis in mice [ 294 ]. Besides, Song et al. discovered HSP90-dependent up-regulation of PUS7 and promotion of metastasis of CRC cells by regulating LASP1 abundance [ 295 ]. Transfer RNA-derived fragment (tRF) is relatively newly discovered small non-coding RNAs (sncRNAs). Pseudouridine-modified mini tRFs containing a 5' terminal oligoguanine (mTOG) can selectively inhibit protein synthesis, while mTOG dysregulation is clinically associated with leukemic transformation and reduced patient survival [ 296 ]. Overall, these findings indicate that altered Ψ can contribute to carcinogenesis by modulating various cellular targets.

Targeting m6A regulators by small molecule modulators in cancer

METTL3 and METTL3-14 complex inhibitors

So far, several METTL3 inhibitors have been identified (Table 2 ). Du et al. screened 1,042 natural products and found quercetin was the most potent METTL3 inhibitor. Quercetin reduced the level of m 6 A in MIA PaCa-2 PAAD cells in a dose-dependent manner. At the same time, quercetin effectively inhibited the proliferation of MIA PaCa-2 and Huh-7 cells [ 297 ]. UZH1a was the first reported METTL3 competitive inhibitor [ 298 ]. Dr. Moroz-Omori et al. further investigated this small molecule compound and confirmed that UZH1a was able to reduce m 6 A levels of mRNA in the leukemia cell line MOLM-13, osteosarcoma U2OS cells, and the immortalized human embryonic kidney cell line HEK293T. Meanwhile, UZH1a had good physical and chemical properties and selectivity, which provided a basis for the development of lead compounds for METTL3-dependent cancers [ 299 ]. Table 2 List of small molecule modulators targeting m 6 A regulators m6A regulators Compounds Structures 50 IC Function Ref METTL3-14-WTAP activator Compound 3 Increasing m 6 A abundance, promotes HEK293 cell proliferation and affecting the cell cycle. [ 300 ] METTL3 and METTL3-14 complex inhibitors Quercetin 2.73μM Reduces m 6 A levels in MIA PaCa-2 PAAD cells, inhibits proliferation of MIA PaCa-2 and Huh7 cells. [ 297 ] UZH1a 7μM Dose-dependent inhibition of m 6 A methylation levels in HEK293T and U2OS cells, selective inhibition of RNA methyltransferase. [ 299 ] Elvitegravir 10μM Enhancing STUB1-mediated proteasome degradation of METTL3, suppresses ESCC metastatic. [ 301 ] UZH2 5nM Reduce m 6 A/A levels of polyadenylated RNA in MOLM-13 and PC-3 cell. [ 302 ] Compound 43n 2.81μM Inhibition of AML cell line proliferation by inhibition of m 6 A levels of mRNA. [ 303 ] STM2457 16.9nM Reduce the growth of AML, increases differentiation and apoptosis, selective inhibit leukemic mRNA m 6 A levels and mRNA translational defects. [ 304 ] SCT-15 Reduce the growth of AML, activates innate immune pathways, and enhances the anti-tumors properties of anti-PD1 therapy to generate a durable antitumor immune response. [ 305 ] FTO inhibitor Rhebarb acid 4.95μM Low cytotoxicity and was able to increase the modification level of intracellular m 6 A mRNA, and the inhibitory effect on ssRNA demethylation occurred in a concentration-dependent manner. [ 306 ] N-CDPCB, 1a Effectively impacts intracellular m 6 A abundance. [ 307 ] Meclofenamic acid 4.6μM /17.4μM Competition with FTO for binding to m 6 A-containing nucleic acids, increased mRNA m 6 A modification levels in HeLa cell. Combined with GE increased m 6 A methylation and induced caspase-related apoptosis in resistant NSCLC cells, downregulated BCRP and MRP7 expression in resistant GE cells. [ 308 , 309 ] FB23, FB23-2 1.9-5.2μM Directly to FTO and selectively inhibits FTO activity, significantly inhibits AML cell lines proliferation and promotes differentiation and apoptosis in vitro . [ 310 ] R-2HG <1μM Increasing the level of m 6 A modification in R-2HG-sensitive leukemia cells, which in turn reduces the stability of MYC/CEBPA transcripts, showed antitumor activity against both glioma and leukemia. [ 311 ] CS1, CS2 <500nM Strong antitumor effects in a variety of cancers, inhibiting LILRB4 expression. Sensitizes leukemic cells to cytotoxicity of T-cells and overcomes immune evasion induced by hypomethylation agents. [ 312 ] FL1 6.55μM Selective inhibition of FTO demethylation. [ 313 ] MO-I-500 4.9μM/8.7μM Increased m 6 A methylation levels. Anticonvulsant activity in vivo at nontoxic doses. Significantly inhibited the survival and colony formation in SUM149-MA cells. [ 314 , 315 ] Tricyclic Benzoic Acid Analogue, 13a Upregulates ASB2 and RARA expression and increases their protein abundance, while downregulating MYC expression and reducing MYC protein abundance. Strong antiproliferative effect on AML cells. [ 316 ] Radicicol 16.04μM Dose-dependent inhibition of FTO demethylation activity. [ 317 ] CHTB 39.24μM CHTB decreases FTO enzymatic activity in a dose-dependent manner and competitively inhibits FTO demethylase activity in vitro . [ 318 ] Entacapone 4μM Effects on glucose production in mouse liver and thermogenesis in adipose tissue via acting on the FTO-FOXO1 regulatory axis. [ 319 ] Nafamostat mesylate 1μM A multi-targeted agent that binds to FTO and inhibits the activity of FTO demethylase. [ 320 ] 18077, 18097 1.43μM/0.64μM 18097 inhibits cell cycle processes and migration of cancer cells upon site-directed binding to FTO, and the epi-transcriptome of BC cells was reprogrammed, especially genes associated with the P53 pathway. [ 321 ] FTO-04 3.4μM Increased m 6 A and m 6 Am levels in GSC. [ 322 ] GSH-bioimprinted nanocomposites (GNPIPP12MA) Targeting the FTO/m 6 A pathway synergizes with GSH depletion to enhance anti-leukemogenesis. Targeting leukemia stem cells selectively. [ 323 ] ALKBH5 inhibitor ALK-04 Compared tumor growth of control and inhibitor-treated mice during immunotherapy, mice treated with ALKBH5 inhibitor significantly reduced tumor growth compared to control. [ 93 ] MV1035 <500μM Reduce CD73 protein expression and significantly reduce A-172 cell migration and Invasion via inhibiting ALKBH5. [ 324 ] Compound 1/2 0.84 μM/1.79 μM Inhibition of cell proliferation in three leukemia cell lines (HL-60, CCRF-CEM and K562) at low micromolar concentrations of inhibitors. [ 325 ] Compound 20m 0.021 μM Compound 20m was highly selective for ALKBH5 and could increase the total level of m6A in cells while effectively stabilizing ALKBH5 in HepG2 cells. [ 326 ] FTO and ALKBH5 inhibitor Compound 12 0.81μM/108.1μM For FTO binding capacity is significantly higher than for other ALKB subfamilies. [ 327 ] IGF2BP1 inhibitor BTYNB 5μM Consistently interference with E2F-driven gene expression and LUAD growth. [ 328 ] Triptonide <200nM Inhibited the growth of human NPC cell in vitro and in vivo via disrupting Lnc-THOR-IGF2BP1 signaling, and TN was not toxic to nasopharyngeal epithelial cells. [ 329 ] 7773 30.45μM Reduced levels of Kras mRNA and protein, decreased kras downstream signaling, and suppressed the pro-oncogenic activity of IGF2BP1. [ 330 ] Cucurbitacin B (CuB) <5μM Directly targets a unique site (Cys253) in the KH1-2 domain of IGF2BP1. CuB showed significant anti-LIHC effect by inducing apoptosis as well as blocking PD-L1 expression. [ 331 ]

Lee et al. discovered the first allosteric inhibitor of the METTL3-14 complex and optimized the compounds by modifications. The optimized compound 43n showed promising enzyme inhibitory activity and anti-proliferation effect on AML cell lines [ 303 ]. Moreover, Yankova et al. identified STM245 and found METTL3-dependent catalytic inhibition by STM2457. They demonstrated crystal structure of STM2457 in complex with METTL3-METTL14. STM2457 exhibited promising anti-AML effects both in vivo and in vitro by reducing m 6 A levels . It can also increase differentiation and apoptosis and target key stem cell subpopulations of AML 304]. STC-15, which has the same scaffold as STM2457, inhibits acute myeloid leukemia progression by inhibiting METTL3, while activating anticancer immunity and producing long-lasting tumor immune responses. In 2022, STC-15, a small molecule oral inhibitor for METLL3, conducted a phase I human clinical trial [ 305 ].

FTO inhibitors

In recent years, many small molecule inhibitors of FTO have been reported (Table 2 ). Chen et al. identified the first potent inhibitor of FTO. The natural product Rhein inhibits FTO by reversibly and competitively binding the catalytic domain and alters m 6 A levels in intracellular mRNA [ 306 ]. However, the author demonstrated that Rhein could also inhibit ALKB homolog 2 (ALKBH2) activity with IC 50 value similar to that for FTO. According to literature, Rhein was also found to inhibit JMJD2 histone demethylases, raising the problem of selectivity. Subsequently, small molecule N-CDPCB, 1a has been proven to be a FTO inhibitor, which can inhibit the demethylation of m 6 A modified mRNA by FTO by binding to a novel FTO binding site. Nonetheless, the selectivity of this molecule has not been tested [ 307 ]. Meclofenamic acid (MA) is a non-steroidal anti-inflammatory drug that selectively inhibits FTO bout not ALKBH5. The binding complex contains a β-hairpin motif, which is a region lacked in ALKBH5. [ 308 ]. Inspired by MA, the same research group designed FB23 based on the structure of FTO/MA. FB23 is much more potent in inhibiting FTO than MA but its in vitro anti-proliferation capacity was not satisfying. Thus, the researchers further modified FB23 and obtained FB23-2 which exhibited increased cellular uptake and anti-proliferative activity. FB23-2 was highly selective towards FTO. It displayed a favorable pharmacokinetic profile and promising therapeutic effects in xeno-transplantation and patient-derived xeno-transplantation (PDX) AML mouse models [ 310 ].

R-2HG is a cancer metabolite produced by mutant isocitrate dehydrogenase 1/2, but Su et al. found that R-2HG could inhibit the proliferation of leukemia cells and exerts in vitro and in vivo anti-leukemia activity. Mechanistically, R-2HG inhibited the demethylase activity of FTO and thus increased the m 6 A modification level of R-2HG-sensitive leukemia cells [ 311 ]. The same group screened from 260,000 compounds and identified CS1 and CS2, which were more potent than previously reported FTO inhibitors (FB23–2 and MO-I-500) in inhibiting AML cell viability. Mechanistically, CS1 and CS2 exerted in vitro and in vivo anti-leukemic effects by inhibiting FTO activity, leading to activation of apoptosis signaling and inhibition of the MYC pathway. CS1/CS2 intervention also significantly decreased the expression of immune checkpoint LILRB4 and increased the sensitivity of AML cells to cytotoxicity of activated T cells. Moreover, the anti-tumor effect of these inhibitors was also confirmed in other cancer types in vitro and in vivo. The high anti-tumor efficacy and negligible toxicity shown by CS1/CS2 small molecule compounds make them promising candidates for treatment of malignant tumors [ 312 ].

Meanwhile, fluorescein and its derivatives are demonstrated to selectively inhibit FTO demethylation and label FTO at the same time [ 313 ]. N- (7,3-Dihydroxy-4- (5-chlorophenyl)-4-furyl) ethanesulfonamide, a compound with aminohydroxyfuranone as the core, is recognized as an FTO inhibitor. Zheng et al. demonstrated that it increased m 6 A modification and regulated some microRNAs that can be used to treat CNS diseases [ 315 ]. Later on, FTO inhibitors with selectivity against ALKBH5 were discovered. Huff et al. designed and synthesized small molecule FTO inhibitors with low micromolar IC 50 's and specificity toward FTO over ALKBH5 and identified FTO-02 and FTO-04. Interestingly, FTO-04 prevented neural spheres formation in patient-derived GSC but not neural spheres derived from healthy neural stem cells, thus is more suitable for clinical application [ 322 ]. Toh et al. developed a strategy that targeted both the 2OG- and nucleotide-binding sites of FTO and identified compound 12 with a good selectivity toward FTO against other ALKB family members especially ALKBH5. Moreover, they preliminarily tested ethyl ester derivative of 12, compound 25, which can be hydrolyzed to 12 in the cell. Compound 25 is not toxic to the cell and is effective in increasing the level of m 6 A modification [ 327 ].

ALKBH5 inhibitor

Unlike FTO, study of ALKBH5 inhibitors is relatively limited (Table 2 ). Based on the nitrogen heterocyclic structure, the small molecules2-[(1-hydroxy-2-oxo-2-phenylethyl) sulfonyl] acetic acid and 4-[[(furan-2-yl)methyl]amino]-1,2-diazinane-3,6-dionekey can inhibit the proliferation of Hl-60, CCRF-CEM and K562 leukemia cell lines at low micromolar concentrations by inhibiting the demethylation activity of ALKBH5. However, there was no growth inhibitory effect in another leukemia cell line, Jurkat, or A-172 cell, suggesting the effect of these compounds are cell-type dependent [ 325 ]. More recently, Fang et al. identified compound 20 m as a ALKBH5 inhibitor, which demonstrated high selectivity towards ALKBH5 rather than FTO or other ALKB subfamily members [ 326 ]. By in silico screening of compounds and structure–activity relationship study on a library of synthesized compounds, Li et al. identified a specific inhibitor of ALKBH5 and named it ALK-04. It didn’t show cytotoxicity in vitro but potentiated GVAX/anti-PD-1 treatment in vivo [ 93 ].

IGF2BP1 inhibitors

To date, IGF2BP1 has been found to accelerate tumor growth and is associated with poor prognosis in solid tumors. Therefore, inhibition of IGF2BP1 may be a promising anti-cancer strategy (Table 2 ) [ 184 , 332 , 333 ]. Simon Müller's team revealed that IGF2BP1 was a post-transcriptional super-enhancer of E2F-dependent transcription in cancer and small molecule BTYNB disrupted E2F-driven gene expression by impairing IGF2BP1-RNA binding. In vivo, BTYNB consistently interfered with tumor growth in mouse model [ 328 ]. Wallis et al. reported a small molecule compound "7773", which directly bound to IGF2BP1 and inhibited its binding to Kras RNA. By reducing Kras protein and other IGF2BP1 targets and downstream signaling, it reversed IGF2BP1's carcinogenic activity [ 329 ]. Trapnide (TN) is a natural small molecule monomer extract. It has been shown that TN blocked the association between LncRNA THOR and IGF2BP1 in NPC cells and down-regulated the expression of Lnc-THOR and IGF2BP1 mRNA targets. In vivo, the growth of subcutaneous NPC xenografts in mice was significantly inhibited by intraperitoneal injection of TN [ 330 ].

These numerous studies have confirmed that some small molecule compounds can influence m 6 A abundance, while testing their ability to impact proliferation of cancer cells.

Conclusions and perspectives

Over the past decades, researchers have devoted their efforts to studying RNA modification in cancer and other diseases. A large number of experimental evidence have accumulated and confirmed the involvement of RNA modification in cancer and potentiation of chemotherapy, targeted therapy and immunotherapy by manipulating RNA modification modulators. Despite the preliminary work, several problems remain to be solved before the transformation of current knowledge into clinic. First, efforts are still needed to further clarify the role of m 6 A modulators in drug resistance. METTL3, FTO, YTHDF1-3, and IGF2BP1-3 are well elucidated to exert oncogenic functions and current evidence suggest that targeting METTL3, WTAP, FTO, ALKBH5 and HNRNPA2B1 are feasible in reversing drug resistance. However, research evidence for several other m 6 A regulators are limited and should be studied more comprehensively in different cancers. m6A regulator inhibitors or activators should be developed for specific cancer type or context after we get a clearer picture of the regulatory network. Second, further investigation of epitranscriptome profiling or modification of certain transcripts in tissues or body fluids may help identify biomarkers for predicting drug resistance or relapse. Third, caution should be taken to carefully examine the side effects of RNA methylation targeted molecules considering their extensive influence on various biological pathways. Moreover, future endeavors should also be given to developing more potent and selective candidate m 6 A modulator inhibitors or activators by structural design, chemical synthesis or library screening to fully understand the impact of targeting RNA modification on cancer and drug resistance. The poor selectivity of some molecules, for example R-2HG, will definitely hamper their use in clinics. In addition, small molecule modulators are mainly studied for METTL3/14, FTO, ALKBH5 and IGF2BP1, drugs for other m6Aenzymes should also be explored and studied.

Thus far, most studies have focused on m 6 A-modified mRNA targets, and the exploration of m 6 A modification in tRNA, rRNA, and ncRNA is relatively few in the field of cancer drug resistance. Therefore, in the future, how m 6 A modification affects the function of tRNA, rRNA, and ncRNA, and how it affects the occurrence of drug resistance through these processes, represents one of the research prospects.

As for other RNA modifications, their research progress is far behind m 6 A. For some, there are only a few modulators identified, like m 7 G and Ψ. Identification of regulators for these modifications and investigation of these RNA modifications and their interplay with other regulatory mechanisms in cancer and drug resistance is worthy of further study.

Currently, several m 6 A modulator inhibitors including STC-15, meclofenamate and entacapone are going through early phases of clinical trial. Although no compounds aimed at inhibiting demethylases or “reader” proteins have yet entered clinical trials, it is foreseeable that in the near future, increasing numbers of small molecule compounds will be explored. However, the fact that some small molecule inhibitors are marketed to treat diverse indications likely complicates their use as pure m 6 A modulators due to potential effects of other targets within the cell. Notably, a recent study reported a natural product inhibitor of m 6 A which could reverse lenvatinib resistance in HCC [ 334 ], which will encourage investigations of m6A related drugs for drug resistance. Future exploration of these inhibitors and/or activators alone or in combination with current anti-cancer strategies holds great promise in surmounting cancer drug resistance in clinical practice.

Abbreviations

Ribosomal RNA 2'-O-methylation

5-azacitidine

5-fluorouracil

5-hydroxymethylcytidine

Adenosine

ALKB homolog 1

ALKB homolog 2

ALKB homolog 2

ALKB homolog 3

ALKB homolog 5

Breast invasive carcinoma

Cucurbitacin B

Cisplatin

Dyskeratosis congenita 1

DNA methyltransferase

Dual-specificity phosphatase 6

Epidermal growth factor receptor

Eukaryotic translation initiation factor 2α kinase 2

Eukaryotic initiation factor 3

Translation initiation factor 3 subunit A

Erb-b2 receptor tyrosine kinase 2

Esophageal squamous cell carcinoma

N6 formyl adenosine

Fat mass and obesity-associated protein

Gastrointestinal stromal cancers

Glutaminase 1

Heparin binding growth factor

N6 hydroxymethyl adenosine

Heterogeneous nuclear ribonucleoproteins

Head and neck squamous cell carcinoma

Intrahepatic cholangiocarcinoma

IGF2 mRNA-binding proteins

Just proximal to the X-inactive specific transcript

Long non-coding RNA

Lung squamous-cell carcinoma

N1-methyladenosine

3-methylcytosine

5-methylcytosine

N6-methyladenosine

N6,2'-O-dimethyladenosine

N7-methylguanosine

Meclofenamic acid

Multidrug resistance

Methyltransferase-like 1

Methyltransferase-like 14

Methyltransferase-like 16

Methyltransferase-like 2

Methyltransferase-like 2A

Methyltransferase-like 3

Methyltransferase-like 5

Methyltransferase-like 6

Methyltransferase-like protein 7A

Methyltransferase-like protein 7B

Methyltransferase-like 8

Mitofusin 2

MicroRNA

Multiple myeloma

Messenger RNA

Multidrug transporter1

Methyltransferase complex

5' terminal oligoguanine

Nanog homeobox

Natural killer/T-cell lymphoma

Sun RNA methyltransferases

Oxaliplatin

Poly (ADP-ribose) polymerase1

Phosphoinositide dependent kinase-1

Patient-derived xeno-transplantation

Pseudouridine synthases

RAS-associated protein 1B

RNA binding motif protein 15

RNA binding motif protein X-linked

Relapse-free survival

Ribosomal RNA

S-adenosylmethionine

Small non-coding RNA

Small nucleolar non-coding RNA

Small nuclear RNA

SaikosaponinD

Single-Stranded RNA

Tamoxifen

Ten-eleven translocations

Tyrosine kinase inhibitors

Temozolomide

Trapnide

Transfer RNA-derived fragment

Transfer RNA methyltransferase 140

Transfer RNA methyltransferase 141

Transfer RNA methyltransferase 82p

Transfer RNA methyltransferase 8p

tRNA methyltransferase activator subunit 10C

tRNA methyltransferase activator subunit 6

tRNA methyltransferase activator subunit 61A

tRNA methyltransferase activator subunit 61B

Transfer RNA

Ubiquitin-specific protease1

Vir like m 6 A methyltransferase associated

WD repeat domain 4

Wilms tumor 1-associating protein

Y-box binding protein 1

YT521-B homology

Yin Yang 1

Zinc finger CCCH-type containing 13

Zinc finger CCHC-type containing 4

Pseudouridine

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Lu Tang and Hua Tian contributed equally to this work.

Acknowledgements

The authors would like to express their gratitude to all participants and relevant personnel for their contribution to this study.

Authors’ contributions

Lu Tang was a major contributor in writing the manuscript. Hua Tian have made substantial contributions to the conception. Qi Min, Huili You, Mengshuang Yin and Liqiong Yang searched literature and drawings.Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Shuai Deng, Xiaobing Li, Meijuan Chen, Li Gu and Yuhong Sun conducted and critically reviewed the article.Jing Shen edited and checked the manuscript. Zhangang Xiao and Wanping Li checked the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.

Funding

This work was supported by National Natural Science Foundation of China (No. 81972643 and 82172962).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors consent to publication of the present manuscript.

Competing interests

The authors declare no competing interests.

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