The role of abnormal epigenetic regulation of small GTPases in glioma (Review).

Introduction

Brain tumors are one of the most severe types of malignant tumors, due to their poor prognosis, and serious impact on quality of life and cognitive function. Glioma accounts for ~30% of all primary brain tumors and 80% of malignant brain tumors ( 1 , 2 ). Meanwhile, glioblastoma (GBM) is the most aggressive malignant glioma and constitute ~49% of malignant brain tumors ( 3 , 4 ). The main treatment methods for glioma are surgical resection combined with adjuvant radiotherapy and chemotherapy ( 5 ). Although clinicians and researchers have explored new treatment approaches, patient survival has not yet been markedly improved ( 6 ). Glioma has obvious heterogeneity due to the fact that it can originate from different precursor cells, which complicates treatment ( 7 , 8 ). Based on the similarity of tissue morphology to that of normal brain cells, glioma is divided into different types, including astrocytoma, oligodendroglioma, oligoastrocytoma, ependymoma, and neuronal and mixed neuronal-glial tumors ( 8 , 9 ). However, there are two major disadvantages of the histological classification system; one is the obvious interobserver variability and the other is the ability to accurately predict prognosis in patients with glioma ( 9 ). To overcome these shortcomings, the World Health Organization (WHO) classification criteria of tumors of the central nervous system (CNS) underwent revisions in 2016 ( 10 ). For the first time, the WHO classification criteria used a combination of histological and molecular features to diagnose CNS tumors ( 10 ). In addition, with the development of new diagnostic technologies, an increasing number of molecular markers [including TERT promoter mutations and epidermal growth factor receptor ( EGFR ) amplification] are being introduced into diagnostic criteria, which are beneficial for more precise classification ( 11 ). These molecular markers are conducive to the accurate prediction of patient prognosis and personalized treatment. With in-depth research on the pathogenesis of glioma, novel molecular markers have emerged, including certain members of the small guanosine triphosphate (GTP)ases ( 12 - 14 ).

The small GTPases, also known as the small G proteins or RAS superfamily, is a large protein family, which can be roughly divided into five subfamilies, namely the RAS subfamily, RHO subfamily, RAB subfamily, ADP-ribosylation factor (ARF) subfamily and RAN subfamily ( 15 ), which have similar modes of action. They are binary molecular switches that can cycle between an active GTP-bound conformation and an inactive guanosine diphosphate (GDP)-bound conformation ( 16 ). This process is strictly controlled by guanine nucleotide exchange factors that facilitate GDP dissociation, GTPase-activating proteins that stimulate GTP hydrolysis, and guanine nucleotide dissociation inhibitors that form soluble complexes with small GTPases by shielding their lipid ( 17 , 18 ). These small GTPases participate in most cellular biological processes, including differentiation, proliferation, cell migration, apoptosis, vesicle and organelle dynamics and transport, nuclear dynamics and regulation of the cytoskeleton ( 15 , 19 ). The mutation and abnormal expression of genes encoding small GTPases serve important roles in multiple diseases, including glioma ( 12 , 20 - 32 ). To investigate structural alterations in small GTPase genes in patients with glioma, a comprehensive analysis was performed utilizing data from Glioma (MSK, Clin Cancer Res 2019) and Merged Cohort of LGG and GBM (TCGA, Cell 2016) in cBioPortal ( https://www.cbioportal.org ) ( 33 ). The results demonstrated that the incidence of changes in small GTPase gene structure is considered to be low in glioma ( Fig. 1 ) ( 33 ). Several studies have shown that the abnormal expression of genes encoding small GTPases is often influenced by epigenetic regulation in glioma ( 34 - 66 ) ( Tables I and II ). To elucidate the evolutionary relationships among subfamily members, phylogenetic analysis was performed using MEGA11 ( 67 ) ( Fig. 2 ).

Epigenetic regulation is defined as an inheritable change in gene activity without significant alterations in genomic sequences ( 68 ), and it is a dynamic and reversible process. Epigenetic modifications are important for normal tissue growth, and the development and regulation of temporal and spatial expression of genes ( 69 ). The abnormal epigenetic regulation of genes participates in the initiation, development and maintenance of various diseases, including neoplasms ( 70 - 77 ). Epigenetic modifications include DNA methylation, histone or chromatin post-translational modifications (PTMs) and non-coding RNA (ncRNA) regulations ( 78 ).

DNA methylation is the most quintessential epigenetic modification, which is able to regulate gene expression, genomic stability and chromatin structure ( 69 , 79 ). DNA methylation mainly occurs on CpG sites, and higher frequency CpG sites are known as CpG islands, which are usually unmethylated ( 80 - 82 ). In addition, the abnormal hypermethylation of promoter CpG islands is able to silence tumor suppressor genes that contribute to tumorigenesis ( 83 ). DNA methyltransferases (DNMTs) and ten-eleven translocation proteins serve important roles in CpG methylation sites ( 84 , 85 ). Nucleosomes are the most basic units of chromatin, which are formed by DNA strands wrapping around histone octamers ( 86 ). DNA methylation and histone PTMs synergistically regulate chromatin structure and gene regulation ( 87 , 88 ). The majority of histone PTMs occur on the N- or C-terminal tails of histones that extend away from the nucleosome core particle, including methylation, acetylation, ubiquitylation, phosphorylation, SUMOylation, ADP ribosylation, citrullination and biotinylation ( 78 , 89 ). For histone PTMs, most studies have focused on acetylation, and the methylation of lysine residues on H3 and H4 ( 78 , 90 - 92 ). Different histone PTMs have different biological functions ( 93 ). For example, abnormal H3K27me3 can lead to the inactivation of tumor suppressor genes (such as SOX7 and KLF6 ) ( 90 ). Conversely, the dysregulation of H3K27ac can increase the expression levels of oncogenes (such as BCL6 and BCL11A ) ( 91 , 92 ).

ncRNAs also serve an important role in epigenetic regulation. The vast majority of the genome cannot encode proteins and is transcribed into RNA termed ncRNA ( 94 ). ncRNAs can be divided into two categories based on the number of bases: Small ncRNAs and long ncRNAs (lncRNAs) ( 95 ). Small ncRNAs include Piwi-interacting RNAs, small interfering RNAs, microRNAs (miRNAs/miRs) and some bacterial regulatory RNAs ( 96 ). lncRNAs comprise linear lncRNAs and circular RNAs (circRNAs) ( 97 ). The most extensively studied small ncRNAs are miRNAs, which regulate 60% of protein-coding genes through complementarily binding to the 3′UTR of target mRNAs leading to their degradation or translational repression ( 98 , 99 ). miRNAs can exert both anticancer and pro-cancer functions depending on its target genes and the cell context. lncRNAs measure >200 nucleotides in length and have a low sequence conservation among species ( 100 , 101 ); however, they are more tissue-specific than mRNAs ( 102 ). lncRNAs can biologically function as chromatin regulators, enhancers, ncRNA sponges and molecular scaffolds, among others, in the nucleus or cytoplasm ( 78 ). circRNAs are produced through the back-splicing of linear transcripts and have circular structures that make them insensitive to exonuclease; they also have a higher stability than linear RNAs ( 103 , 104 ). The similarity between circRNAs and lncRNAs lies in their obvious tissue specificity, with the difference being that circRNAs are relatively conserved in evolution. The forms in which circRNAs function are diverse. For example, they serve as adsorption sponges for miRNAs ( 105 ), and protein scaffolds or templates for translation, among others ( 106 ). The abnormal expression of lncRNAs and circRNAs can disrupt their biological functions leading to oncogenesis ( 107 ).

Small GTPases, as important biomolecules, serve vital roles in the development of glioma; however, they rarely undergo changes in gene structure in glioma, which indicates that epigenetic regulation may be involved in regulating their abnormal expression. Due to the dynamic and reversible nature of epigenetic regulation, they have the potential to become therapeutic targets. In addition, ncRNAs can be released from tumors into the blood and urine, and thus may serve a role as diagnostic and prognostic biomarkers, since these samples can be obtained through non-invasive means. The aforementioned advantages have led to extensive research being conducted to elucidate the mechanism underlying the epigenetic regulation of small GTPases in glioma ( 34 - 66 , 108 - 111 ) ( Tables I and II ; Fig. 3 ). In order to promote clinical translation and offer references for follow-up studies, these studies were reviewed herein.

RAS family

The RAS subfamily contains 35 members, six of which are mentioned in the current review, namely KRAS , NRAS , RRAS , RAS-associated protein-1B ( RAP1B ), RHEB and RAS like protein family member 10A ( RASL10A ) ( Fig. 2 ) ( 34 - 40 , 42 - 46 , 112 ).

There are three classic RAS genes, HRAS , NRAS and KRAS , which encode four highly homologous protein isoforms (HRAS, NRAS, KRAS4A and KRAS4B) ( 113 ). It is well known that RAS genes are proto-oncogenes, and ~19% of patients with cancer carry RAS mutations ( 114 ). Although RAS signaling pathways are often abnormally activated in patients with GBM, the RAS mutation frequency is very low ( 115 ). As is widely recognized, RAS protein is the most critical downstream effector of EGFR, which can directly activate RAS via GRB2/SOS recruitment ( 116 ). Subsequently, the RAF-MEK-ERK1/2 signaling cascade is activated, which can regulate cell proliferation, differentiation, motility, and survival ( 117 ). Abnormal EGFR often leads to aberrant RAS activation ( 118 ). Studies have demonstrated that 57.4% of patients with GBM carry EGFR amplifications or mutations, and EGFR variant III (EGFRvIII) has been reported in 25-33% of patients with GBM ( 119 , 120 ). EGFRvIII exhibits ligand-independent constitutive activation and can directly activate RAS, which results in aberrant RAS activation ( 120 ). Some studies have also shown that the upregulation of wild-type RAS can promote oncogenesis, including in glioma ( 121 , 122 ). This implies that combined therapy targeting mutant EGFR and inhibiting RAS expression could potentially improve glioma treatment outcomes.

Certain studies have shown that downregulated miRNAs, which are negative regulatory factors of RAS genes, may contribute to overactivated RAS signaling pathways in glioma ( 34 - 38 ). Wang et al ( 34 ) reported that miR-181d is downregulated and KRAS is upregulated in glioma tissues compared with those in normal tissues. In addition, this previous study confirmed that miR-181d can directly target KRAS to restrain RAS/RAF/MEK/ERK and RAS/PI3K/PTEN/AKT signaling pathways, which promote apoptosis and cell cycle arrest, and restrain the proliferation of glioma cells. Furthermore, Wang et al ( 35 ) showed that the expression of miRNA let-7a is lower in high-grade glioma compared with that in low-grade glioma, and patients with a low level of miRNA let-7a have a poor prognosis. In addition, the results of this study suggested a negative association between miRNA let-7a and KRAS expression in glioma. Furthermore, it was reported that miRNA let-7a may directly target KRAS to suppress downstream signaling pathways, which affect proliferation, apoptosis, migration and invasion in glioma cells independent of their PTEN mutation status ( 35 ).

RRAS is a close relative of the classic RAS protein ( 123 ); however, unlike the classic RAS gene, the RRAS gene rarely undergoes mutations in human cancer ( 123 ). Certain studies have reported that the aberrant expression of RRAS contributes to tumors of the human CNS ( 124 , 125 ). Shi et al ( 36 ) reported that the expression levels of miR-124 are clearly reduced in glioma compared with those in normal tissues, and a negative correlation has been observed between the expression of miR-124 and that of RRAS/NRAS . This previous study also revealed that RRAS and NRAS are the direct targets of miR-124, and the re-expression of miR-124 can block the PI3K/AKT and RAF/ERK1/2 pathways, which are major downstream effectors of RRAS and NRAS molecules ( 36 ). These results ultimately resulted in the inhibition of cell proliferation, invasion and angiogenesis, and increased the chemosensitivity of glioma cells. In addition, it was revealed that RRAS and NRAS can synergistically regulate vascular endothelial growth factor transcriptional activation ( 36 ). Zhang et al ( 37 ) reported that activated receptor tyrosine kinases, mesenchymal to epithelial transition factor (MET), EGFR and platelet-derived growth factor receptors might be capable of decreasing the expression levels of miR-134 in glioma. Furthermore, it was confirmed that MET could suppress the expression of miR-134 via mitogen-activated protein kinase and Krüppel-like factor 4. A reduction in the expression levels of miR-134 was shown to lead to upregulation of KRAS and the transcription factor signal transducer and activator of transcription 5B, as targets of miR-134 ( 37 ). These aforementioned processes may promote GBM cell proliferation and GBM stem cell (GSC) neuro-sphere formation, and block the differentiation of GSCs ( 37 ). Zhao et al ( 38 ) also revealed the antitumor effects of miR-134 by targeting KRAS in glioma.

RAP1 also belongs to the RAS subfamily and is involved in regulating cell adhesion, cell-cell junctions, migration and polarization ( 126 ). RAP1 possesses two isoforms: RAP1A and RAP1B; RAP1A mainly participates in maintaining cell-cell junctions, and RAP1B mainly regulates dynamic changes in cell-cell junctions ( 127 , 128 ). Previous studies have shown that the upregulation of RAP1B can contribute to the development of various types of cancer ( 129 , 130 ). She et al ( 39 , 40 ) reported that miR-181 subunits miR-128 and miR-149 are lowly expressed, and RAP1B is highly expressed in glioma, as a target of miR-181 subunits (miR-128 and miR-149). miR-181 subunits miR-128 and miR-149 have been shown to suppress cell proliferation and invasion, and affect the cytoskeleton remodeling of glioma cells by controlling RAP1B ( 39 , 40 ). Notably, miR-181 subunits miR-128 and miR-149 may enhance the chemosensitivity of glioma cells for temozolomide by targeting RAP1B ( 39 , 40 ). Li et al ( 41 ) indicated that the expression levels of lncRNA MALAT1 and RAP1B are increased, and those of miR-101 are decreased in glioma cell lines, compared with those in normal human astrocytes (NHAs). Furthermore, this previous study elucidated that lncRNA MALAT1 serves as a sponge of miR-101 to decrease miR-101 expression, and then increases RAP1B expression, which can promote the proliferation and block the apoptosis of glioma cell lines ( 41 ). Wan et al ( 42 ) identified that transient receptor potential cation channel, subfamily M, member 7 facilitates the proliferation and invasion of glioma cells by suppressing miR-28-5p targeting RAP1B .

RHEB is found in species from yeast to humans, and has only a single effector, the target of rapamycin (TOR) Ser/Thr kinase ( 15 , 131 ). Aberrantly activated RHEB/mammalian TOR complex 1 (mTORC1) signaling is associated with proliferative disorders and tumorigenesis ( 132 ). RHEB upregulation is rarely observed in glioma cell lines compared with in normal brain cells ( 133 ); however, the aberrantly activated RTK/PI3K/AKT/mTOR signaling pathway serves a critical role in the development of glioma ( 134 , 135 ). RHEB is a key activator of TOR, and targeting RHEB may therefore suppress the progression of glioma by blocking mTOR signaling ( 15 ). Besse et al ( 43 ) demonstrated that miR-338-5p, which is a brain-specific miRNA, may partially exert antitumor effects by suppressing RHEB in glioma. Kalhori et al ( 44 , 45 ) reported that miR-579, miR-548x and miR-4698 are able to simultaneously target AKT1 and RHEB to inhibit proliferation, migration and process of the cell cycle, and promote apoptosis in glioma. However, these studies are limited to cell lines and lack clinical validation.

RHO family

The RHO subfamily has 20 members and can be divided into six groups: RHO subfamily (RHOA, RHOB and RHOC), RAC family small GTPase (RAC) subfamily (RAC1, RAC2, RAC3 and RHOG), cell division cycle 42 (CDC42) subfamily (CDC42, WRCH1, TC10, CHP and TCL), RND subfamily (RND1, RND2 and RND3), RHO BTB subfamily (RHOBTB1, RHOBTB2 and RHOBTB3) and MIRO subfamily (MIRO1 and MIRO2) ( 136 ). Their biological functions mainly include the regulation of cytoskeletal rearrangement, cell motility, cell polarity, axon guidance, vesicle trafficking and the cell cycle process ( 137 ). Dysfunctional RHO GTPase has been reported to be involved in the development of various diseases, including cancer, immunological disorders and neurological abnormalities ( 136 ). The present review mainly focuses on the abnormal epigenetic regulation of RHOA , RHOB , RHOG , RAC1 and CDC42 in glioma ( 47 - 52 ).

The most well-known function of RHOA is to regulate actin-myosin contractility and stress fiber formation, which drive cell motility and invasion, suggesting that RHOA signaling may be implicated in tumor invasion and metastasis ( 138 ). In addition, studies have established that the RHOA/ROCK signaling pathway can regulate the migration and invasion of glioma ( 139 - 141 ). Several research groups have concentrated on elucidating the mechanisms by which ncRNAs control RHOA expression in glioma. Tang et al ( 50 ) reported that leucine-rich repeat ( LRR ), a brain-specific gene, is able to upregulate miR-185, and indicated that the expression levels of LRR and miR-185 are lower in glioma tissues than those in normal tissues. This previous study also elucidated that miR-185 can suppress the invasion of glioma cells and the expression of vascular endothelial growth factor A by directly targeting CDC42 and RHOA ( 50 ). Notably, a significantly positive association has been reported between the expression of LRR and miR-185, and patient prognosis ( 50 ). RHOB regulates actin organization and vesicle transport, which is similar to that of RHOA and RHOC ( 142 ); however, RHOB mainly exerts anticancer function in several types of cancer ( 143 - 145 ). RHOA, RHOB and RHOC have homologous effector domains and the effectors of RHOA can interact with RHOB in a specific environment ( 146 ). RHOB may block the tumor-promoting function of RHOA and RHOC through competitive binding ( 146 ). The abnormal downregulation of RHOB has been shown to contribute to the progression of certain types of cancer, including glioma ( 25 , 51 , 147 , 148 ). Chen et al ( 51 ) reported that miR-19a expression is increased in glioma tissues, and glioma cell proliferation and invasion are promoted by miR-19a. Furthermore, it has been revealed that miR-19a performs cancer-promoting functions by directly targeting RHOB ( 51 ).

The RAC subfamily contains four members, namely RAC1, RAC2, RAC3 and RHOG ( 149 ). The RAC subfamily regulates membrane ruffling and lamellipodia formation by interacting with effector proteins ( 150 ). RAC1 is one of the most studied members, and it is involved in several types of cellular processes, including cell cytoskeletal reorganization, cell transformation, DNA synthesis, superoxide generation, axonal guidance and cell migration ( 151 ). Numerous studies have shown that RAC1 participates in cell transformation and tumor progression ( 152 - 154 ). Sun et al ( 48 ) reported that miR-137 expression is reduced in glioma tissues and that it is negatively correlated with RAC1 in glioma cell lines. It has also been reported that miR-137 hinders human glioma cell proliferation by directly targeting RAC1 ( 48 ). Subsequently, Qin et al ( 49 ) revealed that miR-142 can suppress the migration and invasion of glioma by targeting RAC1 . A previous study also indicated that RHOG is involved in regulating the development of glioma ( 155 ). Cai et al ( 52 ) demonstrated that there is a negative correlation between the expression levels of miR-124-3p and RHOG in patients with glioma. It was also revealed that miR-124-3p can block the viability and motility of GBM by directly targeting RHOG ( 52 ).

As members of a RHO subfamily, CDC42 regulate the actin cytoskeletal architecture ( 156 ). CDC42 has also been shown to be involved in the establishment of cell polarity ( 157 ). CDC42 is upregulated in various types of cancer, and is closely associated with oncogenic transformation, invasion and tumorigenesis ( 22 , 158 , 159 ). Shi et al ( 47 ) revealed that the expression levels of miR-29a/b/c are reduced with an increase in tumor grade and indicated that they have a good prognostic value. They also showed that miR-29a/b/c directly targets CDC42 , and there is a negative correlation between the expression of miR-29a/b/c and that of CDC42 in patients with glioma ( 47 ). In addition, miR-29a/b/c could suppress glioma invasion by blocking the CDC42-PAK pathway ( 47 ).

RASL10A, also known as Ras-related protein on chromosome 22 ( 46 ), is member of the more distal branches of the RAS family and was designated as a 'distal-RAS' by Bernal Astrain et al ( 112 ). However, phylogenetic analysis revealed its closer affinity to the RHO subfamily; therefore, the present study has elaborated on this ( Fig. 2 ). The RASL10A gene is located on a region of chromosome 22, which frequently undergoes loss of heterozygosity in human cancer and RASL10A is considered a tumor suppressor gene ( 160 ). Schmidt et al ( 46 ) reported that the mRNA levels of RASL10A are reduced in most glioma tissues compared with those in normal tissues, with few RASL10A mutations and allelic deletions observed ( 46 ). This finding is consistent with the previously mentioned results, which revealed that the incidence of changes in small GTPase gene structure is considered to be low in glioma ( Fig. 1 ). In addition, it has been reported that the hypermethylation of the RASL10A 5′-CpG island and hypoacetylation of H3 and H4 contribute to a low RASL10A mRNA level ( 46 ). Notably, RASL10A mRNA level can serve as a prognostic marker in glioma ( 46 ).

RAB family

The RAB family is the largest subgroup of the RAS superfamily, which comprises ~70 members that function as controllers of vesicle traffic, membrane tethering and fusion ( 161 - 163 ). Each RAB has its own specific membrane localization, which is beneficial for controlling the specificity and directionality of membrane trafficking pathways ( 161 ). The abnormal expression and activity of RAB s are associated with the occurrence and progression of various tumors ( 164 - 168 ). RAB1A , RAB3B , RAB5A , RAB10 , RAB21 , RAB22A , RAB27B , RAB23 and RAB18 are mentioned in the present review ( 53 - 65 ).

RAB1 is able to regulate dynamic membrane trafficking between the endoplasmic reticulum (ER) and Golgi apparatus, and evidence has shown that it is also involved in nutrient sensing and signaling, cell migration and the presentation of cell-surface receptors ( 169 ). RAB1 contains two isoforms, RAB1A and RAB1B, which share 92% amino-acid sequence homology and are functionally interchangeable ( 170 , 171 ). RAB1A and RAB1B are mainly located at the ER and the Golgi apparatus membrane, and are also observed in lipid rafts and autophagosomes ( 172 ). The dysregulation of RAB1A and RAB1B are associated with the initiation and development of multiple types of cancer, including glioma ( 173 - 176 ). Quan et al ( 53 ) reported that miR-1202 is decreased in glioma, and the expression levels of miR-1202 are negatively correlated with RAB1A . Furthermore, it was revealed that that miR-1202 can suppress the proliferation, and induce ER stress and apoptosis in glioma by directly targeting RAB1A ( 53 ). Subsequently, Xu et al ( 54 ) demonstrated that lncRNA DANCR is increased in glioma compared with that in normal tissues. It was also revealed that lncRNA DANCR functions as competing endogenous RNA by directly targeting miR-634, and there is an inverse correlation between the expression levels of lncRNA DANCR and miR-634 in glioma tissues ( 54 ). This previous study also verified that lncRNA DANCR promotes glioma cell proliferation through the lncRNA DANCR/miR-634/ RAB1A axis ( 54 ).

RAB5 is able to mediate intracellular trafficking, both at the level of receptor endocytosis and endosomal dynamics ( 177 ). RAB5 comprises RAB5A, RAB5B and RAB5C, which can be separately recognized by diverse kinases, but there are no differences in their function in endocytosis ( 178 ). Previous studies have indicated that RAB5A is also implicated in the regulation of autophagy ( 179 , 180 ). The abnormal expression of RAB5A has been shown to be associated with the initiation and development of various types of cancer, including glioma ( 27 , 167 , 181 , 182 ). Fu et al ( 55 ) confirmed that lncRNA MALAT1 is elevated in glioma tissues. Notably, lncRNA MALAT1 enhances the proliferation of glioma cells by activating autophagy ( 55 ) and it partially achieves the aforementioned functions through the lncRNA MALAT1/miR-101/ RAB5A axis ( 55 ). Similarly, Gao et al ( 56 ) revealed that another lncRNA TP53 target 1 (TP53TG1) is clearly increased in glioma tissues and strengthens the radioresistance of glioma cells by enhancing autophagy through the lncRNA TP53TG1/miR-524-5p/ RAB5A axis. Wu et al ( 58 ) demonstrated that lncRNA cancer susceptibility 19 is clearly increased in glioma tissues, and promotes the proliferation, migration and invasion of glioma cells through the miR-454-3p/ RAB5A axis. Zhang et al ( 57 ) showed that propofol hinders glioma cell proliferation and metastasis by regulating the circRNA non-SMC condensin I complex subunit G/miR-200a-3p/ RAB5A axis.

RAB10 is mainly located at the ER and Golgi/Trans-Golgi network ( 183 - 185 ). Moreover, it is associated with endosomes/phagosomes and primary cilia ( 186 , 187 ). RAB10 is mainly involved in regulating ER dynamics and morphology, polarized trafficking, establishment of basement membrane polarity and tubular endosome formation ( 183 , 188 - 190 ). Dysregulation of RAB10 has been shown to be associated with the initiation and progress of various types of cancer ( 191 , 192 ). Zhang et al ( 60 ) verified that circ-PTN expression is increased and that of miR-432-5p is decreased in glioma. In addition, it was reported that circ-PTN enhances the proliferation, invasion and glycolysis of glioma cells via the circ-PTN/miR-432-5p/ RAB10 axis ( 60 ). By analyzing public databases, Shen et al ( 59 ) revealed that lncRNA PSMB8-AS1 is increased in glioma and is upregulated in glioma cells via NHA. Subsequently, it was indicated that lncRNA PSMB8-AS1 activated by the ETS transcription factor ELK1 enhances glioma cell proliferation by mediating the miR-574-5p/ RAB10 axis ( 59 ). Peng et al ( 61 ) revealed that LINC00152, an oncogene, is increased in glioma and is a valuable prognostic factor. It was also reported that LINC00152 accelerates glioma cell proliferation and invasion through the miR-107/ RAB10 axis ( 61 ).

Eukaryotic cells internalize fractions of cytomembrane, cell surface receptors and diverse soluble molecules from the extracellular fluid through the endocytosis pathway ( 193 ). These are vital to a series of cellular functions, including nutrient absorption, signaling receptor downregulation and antigen processing ( 194 ). RAB5, RAB21 and RAB22 all reside in the early endosome and regulate early endosome dynamics ( 194 , 195 ). RAB23 is also involved in mediating early endosome dynamics and is a negative regulator of hedgehog signaling ( 196 ). Previous studies have revealed that the dysregulation of these genes is able to disturb endosome dynamics, which lead to the occurrence of cancer ( 197 - 200 ). Song et al ( 62 ) reported that circ_0030018 abundance is higher in glioma cell lines compared with that in NHAs. It was subsequently suggested that circ_0030018 accelerates cell proliferation and metastasis, and blocks apoptosis and cell cycle arrest in glioma by regulating the miR-1297/ RAB21 axis ( 62 ). Similarly, RAB22A is regulated by ncRNA in glioma. Xia et al ( 63 ) reported that miR-204-5p expression is reduced in glioma tissues compared with that in normal tissues, and is negatively associated with pathology classification. It has also been shown that miR-204-5p inhibits glioma cell proliferation, migration and invasion by directly targeting RAB22A ( 63 ). Notably, miR-200b can suppress the progression of glioma by targeting a set of RABs ( 65 ). Liu et al ( 65 ) demonstrated that miR-200b, a tumor suppressor, is able to directly target RAB3B , RAB18 , RAB21 and RAB23 . Notably, their expression levels have a good prognostic value ( 65 ). RAB21 and RAB23 can regulate endosome dynamics; RAB3 serves a critical role in the regulation of exocytosis and contains two isoform, RAB3A and RAB3B ( 201 ); RAB18 is a lipid droplet-associated small GTPase, and its abnormal expression disturbs the storage and mobilization of lipids ( 202 ). It is also involved in ER structure maintenance and ER-Golgi trafficking ( 203 , 204 ). These findings indicate that miR-200b inhibits cancer progression by regulating multiple biological processes.

RAB27 is an important regulator of secretory pathways and comprises two isoforms, RAB27A and RAB27B ( 205 ). Notably, it has been reported that RAB27A and RAB27B serve different roles in specific types of secretion by interacting with various effectors ( 205 ). Ostrowski et al ( 206 ) reported that RAB27A and RAB27B are involved in multivesicular endosomes docking at the plasma membrane, but both serve different roles in the exosome secretion pathway via their effectors SLP4 and SLAC2B, respectively ( 206 ). The aberrant regulation of RAB27 is associated with the initiation and progression of cancer ( 207 ). Wang et al ( 64 ) reported that the RAB27B promoter region is hypomethylated in high-grade glioma compared with that in low-grade glioma, and identified a negative association between RAB27B abundance and RAB27B methylation level. Furthermore, it was revealed that RAB27B enhances glioma invasion by activating matrix metalloproteinase-9 ( 64 ). Notably, the RAB27B methylation level is a valuable prognostic factor of glioma ( 64 ).

ARF family

The ARF family mainly controls membrane traffic and organelle structure, and is divided into three classes: Class I (ARF1, ARF2 and ARF3), Class II (ARF4 and ARF5) and Class III (ARF6) ( 208 ). Class I ARFs exist in all eukaryotic organisms and are highly conserved ( 208 ). They are able to mediate the fabrication of various types of 'coat' complexes onto budding vesicles along the secretory pathway, and activate lipid-modifying enzymes ( 209 ). The present review focusses on ARF1.

ARF1 is the most studied mammalian ARF protein, primarily located at the Golgi apparatus ( 210 ). ARF1 mainly regulates the recruitment of effectors, coat protein complex I, adaptor protein 1 and Golgi-associated, γ-adaptin homologs, ARF-interacting proteins on the Golgi apparatus ( 211 ). Several studies have shown that the abnormal expression and activation of ARF1 are involved in the occurrence and progression of cancer ( 212 - 214 ). In a previous study, 40-50% of patients with GBM carried EGFR amplification ( 215 ). López-Ginés et al ( 66 ) explored the correlation between EGFR amplification and the promoter methylation status of 10 genes relevant to GBM. The results revealed that the ARF1 promoter methylation level was lower in the EGFR amplification group compared with that in the group without EGFR amplification; however, the mRNA expression levels of ARF1 were higher in the EGFR amplification group ( 66 ). ARF1 overexpression was also shown to cause metabolic reprogramming, which may promote the progression of glioma ( 66 ).

Clinical application prospects

Gliomas account for the vast majority of primary malignant brain tumors ( 2 ). Although there are a number of novel treatment methods for glioma, most are in the preclinical experimental stage ( 216 ). The current treatment methods for glioma are still limited, and include surgery, radiotherapy and chemotherapy ( 217 ). The efficacy of the treatment methods is unsatisfactory, and patients often exhibit drug resistance, relapse and metastasis ( 218 ). It is urgent to explore new diagnostic and therapeutic methods for glioma. Due to the diversity and importance of the biological functions of small GTPases, an increasing number of studies have focused on them; however, the incidence of changes in small GTPase gene structure is low in glioma ( Fig. 1 ). Numerous studies have focused on exploring the epigenetic regulation of small GTPase genes in glioma. Epigenetic regulation is a dynamic and reversible process, which implies that the reversion of abnormal epigenetic modifications is a good treatment strategy for glioma. These studies not only provide new therapeutic targets and prognostic markers, but also supply new clues for the treatment of glioma.

DNMT inhibitors (DNMTIs)

DNA methylation is more stable than other epigenetic modifications ( 219 ). The hypomethylation of oncogenes and hypermethylation of tumor suppressor genes can disrupt normal gene expression, which promotes the occurrence and development of cancer ( 220 ). However, the treatment methods for the dysregulation of DNA mainly focuses on the high methylation of tumor suppressor genes. DNMTIs, include 5-azacytidine and 5-aza-2′-deoxycytidine, the most important therapeutic drugs for abnormal DNA methylation ( 221 ). These drugs have achieved good therapeutic effects in the treatment of hematological tumors ( 222 ). Isocitrate dehydrogenase ( IDH ) mutations in glioma cause genome-wide DNA hypermethylation ( 9 ). A small sample size study previously demonstrated that 5-azacitidine treatment is suitable for a subset of patients with IDH1/2 -mutated gliomas, particularly those without prior bevacizumab treatment ( 223 ). This previous study also revealed that 5-azacitidine treatment induces adverse effects, with grade 3-4 neutropenia being the most frequently observed, which led to dose reduction and some patients having to receive concomitant granulocyte colony stimulating factor injections during the following cycles ( 223 ). Although this study had a small sample size, its findings still offer valuable clinical insights. Schmidt et al ( 46 ) demonstrated that the mRNA levels of RASL10A were reduced in most glioma tissues compared with in normal tissues, and that the hypermethylation of the RASL10A 5′-CpG island and hypoacetylation of H3 and H4 contributed to a low RASL10A mRNA level. These findings indicated that patients with glioma carrying both IDH1/2 mutations and RASL10A hypermethylation, which enhance the progression of glioma, are more likely to benefit from 5-azacitidine treatment. Complementary to conventional methylation inhibitor therapy, emerging gene editing approaches are being investigated as precision tools against epigenetically aberrant tumors. He et al ( 224 ) reported that the dCas9-TET1 fusion system can successfully remove methyl groups at CpG islands in the ZNF154 promoter region, and inhibit the proliferation and migration of esophageal squamous carcinoma cells. However, their clinical applicability, particularly for glioma treatment, requires further investigation.

Histone deacetylase inhibitors (HDACIs)

DNA methylation and histone PTMs synergistically regulate chromatin structure and gene regulation ( 225 ). Histone methylation and acetylation are the most extensively studied epigenetic modifications ( 225 ). To date, there are no US Food and Drug Administration (FDA)-approved drugs that directly target histone methylation ( 226 ). However, accumulating studies have demonstrated the therapeutic potential of HDACIs against various malignancies, including glioma ( 227 - 230 ). Belinostat is a HDACI that can cross the blood-brain barrier. Xu et al ( 231 ) reported on the possibility of combining belinostat with standard-of-care therapy in GBM. Panobinostat represents the first HDACI approved by the FDA for the treatment of relapsed multiple myeloma ( 232 ). Monje et al ( 229 ) explored the tolerability of systemically administered panobinostat in children with diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma. This study revealed constrained tolerability of panobinostat in pediatric patients with DIPG, and indicated that panobinostat did not improve the OS and PFS of patients with glioma ( 229 ). In addition, Mueller et al ( 230 ) assessed the safety and efficacy of repeated delivery of aqueous panobinostat via convection-enhanced delivery in patients with newly diagnosed DIPG. By contrast, their results demonstrated that patients with DIPG may benefit from this treatment method ( 230 ). But some treatment-related adverse events need to be taken seriously, including muscle weakness, vagus nerve dysfunction and neutropenia ( 230 ). In this previous study, patients with DIPG underwent both postoperative recovery and drug infusion, with temporal overlap between these procedures. Both interventions carry the potential to induce certain adverse effects (such as vagus nerve dysfunction), making it clinically challenging to determine the predominant causative factor. Given these considerations, only grade ≥3 neutropenia was attributed to aqueous panobinostat ( 230 ). Patients with grade ≥3 neutropenia may need to receive concomitant granulocyte colony stimulating factor injections during the following cycles; however, the precise therapeutic safety and efficacy of this strategy require further validation through large-scale cohort studies. As previously mentioned, Schmidt et al ( 46 ) reported that hypoacetylation of H3 and H4 of RASL10A , which is a potential tumor suppressor, can contribute to a low RASL10A mRNA level. Notably, patients with glioma and hypoacetylation of H3 and H4 of RASL10A have a higher chance of benefiting from repeated delivery of aqueous panobinostat via convection-enhanced delivery.

ncRNAs

The most extensively studied small ncRNAs are miRNAs that can exert both anticancer and pro-cancer functions, depending on their target genes and the cell context. Most miRNAs mentioned in the present review target different types of small GTPases and function as anticancer genes. In addition, previous studies have shown that miRNAs have strong and complex functions, and the same miRNA can target the mRNA of different genes and different miRNAs can target the mRNA of the same gene ( 35 , 38 , 65 ). Multiple miRNAs may therefore be available for selection to reverse the abnormal expression of the same gene, and the re-expression of one miRNA may reverse the dysregulation of multiple genes that mediate diverse signaling pathways in glioma. The re-expression of these tumor suppressor miRNAs may be a promising therapeutic approach for glioma. miR-34 is a tumor suppressor that serves an important role in cell proliferation in various types of cancer ( 233 ). MRX34 is a lipid-formulated miR-34 that is currently in phase I testing in patients with solid tumors, and is the first miRNA mimic to enter clinical trials ( 234 ). However, due to the presence of the blood-brain barrier, the treatment of brain tumors is different from that of other tumors. There is a lack of data supporting whether miRNAs can enter the brain tissue through the blood ( 235 ). With technological developments, these limitations are expected to be resolved. For example, biodegradable nanoparticles loaded with miRNA mimics have previously been implanted at the glioma resection site to enable localized therapeutic delivery, which circumvented the delivery bottleneck of miRNA mimics across the blood-brain barrier ( 236 ). Exosomes, liposomes and gold nanoparticles with miRNA mimics may also be used for systemic delivery ( 235 ). These methods may be applied to the miRNAs discussed in the present study, which could reverse the expression of miRNAs and small GTPases to suppress the development of glioma. To date, to the best of our knowledge, no clinical trials have been conducted to investigate the efficacy of miRNA in glioma treatment. However, some studies have shown that serum miRNAs are valuable prognostic factors for glioma ( 237 , 238 ). Compared with tissue biopsies, serum miRNA detection provides a simpler and less painful alternative for patients; however, the diagnostic value of serum miRNAs that target small GTPases in glioma needs to be explored. Furthermore, lncRNA and circRNA are rarely studied as therapeutic tools; however, they are better prognostic and progression markers than miRNAs due to their stability. Some studies have revealed that serum lncRNAs and serum exosome circRNAs are valuable diagnostic biomarkers for glioma ( 239 - 242 ). Notably, LINC00152 may have the potential to become a prognostic marker of glioma; however, further studies are needed to validate its application as a peripheral biomarker for glioma.

Conclusions

The biological functions of small GTPases are diverse, and have an important role in the initiation and development of glioma. Notably, the incidence of changes in small GTPase gene structure is low in glioma; therefore, researchers have focused more on studying their epigenetic regulation. The present study reviewed relevant studies that explored the epigenetic regulation mechanisms of small GTPases in glioma to provide a reference for future research and to promote the clinical translation of relevant study results. Although translating these research achievements into clinical practice requires further research, the findings of the aforementioned studies provide novel prognostic factors for glioma and lay the theoretical groundwork for epigenetic therapeutic approaches in glioma. It is anticipated that progress in epigenetic drug discovery and delivery methodologies will lead to marked improvements in the prognosis of patients with glioma.

Acknowledgments

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

MZ designed the study and wrote the original draft. YH conducted the literature search and study selection. QZ and XZ conducted comprehensive data extraction, data analysis and critical analysis of all literature, subsequently creating standardized tables and figures. JW and LK got funding acquisition and reviewed the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

ADP-ribosylation factor

cell division cycle 42

circular RNAs

central nervous system

DNA methyltransferases

epidermal growth factor receptor

endoplasmic reticulum

glioblastoma

guanosine diphosphate

glioblastoma stem cells

guanosine triphosphate

long non-coding RNAs

mesenchymal to epithelial transition factor

microRNAs

normal human astrocytes

post-translational modifications

RAC family small GTPase 1

RAS-associated protein-1

RAS like protein family member 10A

target of rapamycin

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