Abstract Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed. 

/pdf/epigenetic-regulation-in-the-tumor-microenvironment-2j3rsfbg.pdf

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

Cancer therapy resistance is the main cause of cancer treatment failure. The mechanism of therapy resistance is a hot topic in epigenetics. As one of the most common RNA modifications, N6-methyladenosine (m6A) is involved in various processes of RNA metabolism, such as stability, splicing, transcription, translation, and degradation. A large number of studies have shown that m6A RNA methylation regulates the proliferation and invasion of cancer cells, but the role of m6A in cancer therapy resistance is unclear. In this review, we summarized the research progress related to the role of m6A in regulating therapy resistance in cancers. 

/pdf/the-role-of-m6a-methylation-in-therapy-resistance-in-cancer-16uqbkhi.pdf

The role of m6A methylation in therapy resistance in cancer

N6-methyladenosine (m6A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m6A writers, erasers, and readers, m6A modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m6A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m6A modulation in tumour immunoregulation, and divergent m6A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m6A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m6A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m6A modulation patterns in anti-tumour immune cells are summarized. 

/pdf/m6a-methylation-a-process-reshaping-the-tumour-immune-20emaab1.pdf

m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion

Abstract RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N 6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets. 

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting

RNA methylation is a critical mechanism for regulating the transcription and translation of specific sequences or for eliminating unnecessary sequences during RNA maturation. METTL3, an RNA methyltransferase that catalyzes the transfer of a methyl group to the N6-adenosine of RNA, is one of the key mediators of this process. METTL3 dysregulation may result in the emergence of a variety of diseases ranging from cancer to cardiovascular and neurological disorders beyond contributing to viral infections. Hence, the discovery of METTL3 inhibitors may assist in furthering the understanding of the biological roles of this enzyme, in addition to contributing to the development of novel therapeutics. Through this work, we will examine the existing correlations between METTL3 and diseases. We will also analyze the development, mode of action, pharmacology, and structure–activity relationships of the currently known METTL3 inhibitors. They include both nucleoside and non-nucleoside compounds, with the latter comprising both competitive and allosteric inhibitors.

METTL3 from Target Validation to the First Small-Molecule Inhibitors: A Medicinal Chemistry Journey

The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.


SIGNIFICANCE
The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.

JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA.

The in-depth study of melanoma pathogenesis has revealed that epigenetic modifications, particularly DNA methylation, is a universal inherent feature of the development and progression of melanoma. In the present study, the analysis of the tumor suppressor gene growth arrest-specific transcript 5 (GAS5) demonstrated that its expression was downregulated in melanoma, and its expression level had a certain negative association with its methylation modification level. The promoter of GAS5 presented with detectable CpG islands, and methylation-specific polymerase chain reaction analysis demonstrated that GAS5 was actually modified by methylation in melanoma tissues and cells; however, no methylation modification of GAS5 was detected in normal tissues. Following the treatment of melanoma cells with 5-Aza-2′-deoxycytidine (5-Aza-dC), GAS5 methylation was significantly reversed. The analysis of melanoma cell proliferation revealed that 5-Aza-dC inhibited A375 and SK-MEL-110 cell proliferation in a time-dependent manner. Further analysis of apoptosis demonstrated that 5-Aza-dC significantly increased the apoptosis level of the two cell lines. Moreover, migration analysis of melanoma cells revealed that 5-Aza-dC significantly reduced cell migration. Furthermore, 5-Aza-dC significantly decreased the invasive ability of the two cell lines. However, when the expression of GAS5 was silenced, the effects of 5-Aza-dC on cell proliferation, apoptosis, invasion and migration were not significant. Furthermore, the subcutaneous injection of A375 cells in nude mice successfully resulted in xenograft tumor formation. However, following an intraperitoneal injection of 5-Aza-dC, the volume and weight of xenograft tumors and Ki-67 expression were significantly reduced, and caspase-3 activity and GAS5 expression were enhanced; following the silencing of GAS5, the antitumor effect of 5-Aza-dC was significantly blocked. On the whole, the present study demonstrates that 5-Aza-dC inhibits the growth of melanoma, and its function may be related to the methylation modification of GAS5.

https://www.spandidos-publications.com/10.3892/or.2022.8334/download

5-Aza-dC suppresses melanoma progression by inhibiting GAS5 hypermethylation

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JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA.

5-Aza-dC suppresses melanoma progression by inhibiting GAS5 hypermethylation