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Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.

In cancer, mutational processes act in concert with epigenetic reprogramming to endow malignant cells with hallmark properties that underpin tumorigenesis. Compared with the relatively rigid and slow processes of genetic evolution, the plastic nature of chromatin enables cells to adapt to a changing environment more rapidly. Multiple myeloma is characterised by high levels of inter- and intra-patient heterogeneity at both the genetic and epigenetic levels. Understanding the many layers of genetic and non-genetic evolution and their interplay is crucial to improve patient outcomes. In this shor

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… EP300/CREBBP are acetyltransferases that acetylate thousands of residues on a wide array of histone and non‐histone protein substrates including lysine 27 of histone 3 (H3K27ac). 95 EP300/CREBBP catalytic inhibitors are highly active against MM cells, and trigger pronounced loss of histone acetylation … IMiDs to downregulate MYC and IRF4, 34 and their activity can be further boosted by drugs that increase the activity of the PRC2 complex, which functionally antagonises EP300/CBP. 96 Notwithstanding their promising activity against model systems in vitro and in vivo, clinical development of catalytic (acetyltransferase …

Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanis

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… Functioning in concert with histone acetyltransferases (HATs), HDACs maintain the delicate balance of lysine acetylation/acylation within cells [ 27 ]. … Histone Deacetylases: Functional Roles and Therapeutic Potential Histone deacetylases (HDACs) are epigenetic regulators that influence chromatin organization and gene expression by modulating lysine acetylation in opposition to histone acetyltransferases [ 55 , 56 ]. …

Biosynthesis of anticancer phytochemical compounds and their chemistry.

Cancer is a severe health issue, and cancer cases are rising yearly. New anticancer drugs have been developed as our understanding of the molecular mechanisms behind diverse solid tumors, and metastatic malignancies have increased. Plant-derived phytochemical compounds target different oncogenes, tumor suppressor genes, protein channels, immune cells, protein channels, and pumps, which have attracted much attention for treating cancer in preclinical studies. Despite the anticancer capabilities of these phytochemical compounds, systemic toxicity, medication resistance, and limited absorption re

Breaking into HIV-1's Epigenetic Vault: Cure Strategies to Eliminate the Viral Reservoir.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell's DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. "Shock and Kill" uses latency reversal agents to open the provirus's chromatin, promoting high levels of gene expression that induc

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… This is additionally associated with enrichment of histone acetyltransferases (HATs) like p300/CREB-binding protein (CBP) [ 108 , 109 , 110 ] and the H3K27 demethylase UTX-1 [ 111 ], which work together to “loosen” the interaction between DNA and histone by neutralizing the charge of the histone core …

Epigenetics in myeloproliferative neoplasms.

The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methyl

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… Histone acetylation is reversibly regulated by histone acetyltransferases (writers) and histone deacetylases (HDACs) (erasers). Particularly on histones H3 and H4, acetylation occurs at lysine (K), while HDACs remove acetyl residues from histone tails ( 5 ). … Histone acetyltransferases and HDACs are recruited to target genes with specific factors and regulate gene expression. HDACs can be divided into three classes. …

Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF-1α Positive Feedback Loop.

Nephroblastoma, also known as Wilms tumor (WT), is the most common pediatric renal malignancy. Current treatment regimens exhibit limited efficacy in high-risk patients and are associated with long-term adverse effects. Through gene set enrichment analysis (GSEA) and validation using clinical specimens, we identified aberrant glycolytic activity in WT, which drives lactate accumulation. Lactate is not merely a metabolic byproduct but also a critical epigenetic regulator that mediates histone lactylation; however, its functional role in WT remains uncharacterized. In this study, we found that t

Tuning epigenetics to enhance cancer virotherapy.

Cancer remains a major global health challenge, driving intensive research into novel therapeutic strategies. Oncolytic viruses (OVs) including herpesviruses, adenoviruses and echoviruses, have emerged as promising agents for cancer treatment, with several achieving regulatory approval. These viruses selectively lyse tumor cells and stimulate antitumor immunity. Nevertheless, their efficacy is constrained by limitations such as neutralization by serum factors and tumor cell resistance. Concurrently, epigenetic inhibitors modulate gene expression to suppress tumor proliferation and reshape immu

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… This process is catalyzed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs) 113 . HATs include GNAT (GCN5, PCAF), MYST (MOF, Tip60), CBP/p300, and Rtt109 families, each with distinct roles in transcription and repair 46 , 114 , 115 , 116 . … Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics. 2022;12:4935–4948. doi: 10.7150/thno.73223. 47. Picaud S., Fedorov O., Thanasopoulou A., Leonards K., Jones K., Meier J., et al. …

Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairment

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… However, downregulation or inhibition of α-tubulin acetyltransferases, such as αTAT1, could also be involved in cisplatin-induced α-tubulin deacetylation [ 27 ]. Inhibition of HDAC6 normalized the level of acetylated α-tubulin in the brain. ACY-1083 alone did not have any effect. … Kalebic N, Sorrentino S, Perlas E, Bolasco G, Martinez C, Heppenstall PA (2013) alphaTAT1 is the major alpha-tubulin acetyltransferase in mice. Nat Commun 4: 1962. 10.1038/ncomms2962 28. Kesler SR, Blayney DW. …

Epigenetics-targeted drugs: current paradigms and future challenges.

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifyin

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science.

Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer. In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine-derived phytochemicals curcumin, resveratrol, and berberine. Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy. I

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… CREBBP and EP300, histone deacetylase SIRT3, histone demethylase KDM6A, histone methyltransferase SETD7, and a decrease in histone acetyltransferase HDAC8, and histone methyltransferases WHSC1I, WHSC1II, and SMYD3 in multiple myeloma cells. 68 In addition, treatment with berberine results in the downregulation … Histone acetylation is deeply involved in transcriptional activation and is regulated by two opposing classes of enzymes, histone acetyltransferases (HATs) and deacetylases (HDACs). 192 HATs perform acetylation of specific lysine residues and induce enhanced gene transcription. …

Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications.

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exe

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… Two classes of enzymes, histone acetyltransferases (HATs) and HDACs, work against each other to acetylate and deacetylate proteins, respectively. Both an abnormal expression of HDACs and aberrant protein acetylation, especially histones, have been linked to cancer. … Moreover, EGCG was shown to inhibit the activity of histone deacetylases (HDACs) that counteract the introduction of acetyl groups to histone proteins via histone acetyltransferases (HATs). …

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases.

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the u

Toxicity studies of WY-14,643 (CAS No. 50892-23-4) administered in feed to male Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters.

Wy-14,643 was selected for inclusion in a series of studies on peroxisome proliferators because it is known to produce considerable peroxisome proliferation and hepatocarcinogenicity in rats. Male Sprague-Dawley rats were exposed to Wy-14,643 (greater than 98% pure) in feed for up to 3 months; male B6C3F1 mice and male Syrian hamsters were exposed to Wy-14,643 in feed for 2 weeks or up to 3 months. Animals were evaluated for clinical pathology, plasma concentrations of Wy-14,643, reproductive system effects, cell proliferation and peroxisomal enzyme analyses, and histopathology. Single and mul

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immun

Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs.

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to m

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome.

Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chrom

Histone Modifier KANSL2 является практически осуществимым биомаркером в Мультимиломе.

Эпигенетические отклонения являются ключевыми движущими силами множественной миеломы, однако адресная терапия, использующая эпигенетические изменения, еще не установлена. Объединяя клинические и молекулярные наборы пациентов с множественной миеломой с непредвзятым генетическим экраном в vivo, мы определили подгруппу 2 (KANSL2) КАТ8, регулирующую комплекс NSL, как гистонную послетрансляционную модификацию, связанную с онкогене. Высокое выражение KANSL2 было связано с неблагоприятным прогнозом у пациентов с множественной миеломой. Генетические модели " наживы " и " потери функцион

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… Histone acetyltransferases (HAT) convert compact chromatin into a relaxed state, thereby facilitating accessibility for transcription factors and enhancing gene expression ( 7 ). … CBP/p300 acetyltransferase activity in hematologic malignancies. Mol Genet Metab 2016;119:37–43. 4. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood 2018;132:587–97. 5. …

Metagenomic Profiling of Oral Microbiome Dynamics During Chemoradiotherapy in Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: We explored the interaction between the oral microbiome and the development of radiation-induced mucositis in patients with head and neck squamous cell cancer (HNSCC) undergoing chemoradiotherapy (CRT). We prospectively studied the oral microbiome and compared it to healthy controls. Additionally, we compared patients with low-grade (LGM) vs. high-grade mucositis (HGM). METHODS: Ten HNSCC patients scheduled for CRT were included. Saliva samples were characterized prior to, during, and nine months after CRT using metagenomic sequencing. We similarly characterized samples from seven

Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies.

Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lympho

MMSET: role and therapeutic opportunities in multiple myeloma.

Recurrent chromosomal translocations are central to the pathogenesis, diagnosis, and prognosis of hematologic malignancies. The translocation t(4; 14)(p16; q32) is one of the most common translocations in multiple myeloma (MM) and is associated with very poor prognosis. The t(4; 14) translocation leads to the simultaneous overexpression of two genes, FGFR3 (fibroblast growth factor receptor 3) and MMSET (multiple myeloma SET domain), both of which have potential oncogenic activity. However, approximately 30% of t(4; 14) MM patients do not express FGFR3 and have poor prognosis irrespective of F