Epigenetic targeting of autophagy for cancer: DNA and RNA methylation

Abstract

Autophagy, a crucial cellular mechanism responsible for degradation and recycling of intracellular components, is modulated by an intricate network of molecular signals. Its paradoxical involvement in oncogenesis, acting as both a tumor suppressor and promoter, has been underscored in recent studies. Central to this regulatory network are the epigenetic modifications of DNA and RNA methylation, notably the presence of N6-methyldeoxyadenosine (6mA) in genomic DNA and N6-methyladenosine (m6A) in eukaryotic mRNA. The 6mA modification in genomic DNA adds an extra dimension of epigenetic regulation, potentially impacting the transcriptional dynamics of genes linked to autophagy and, especially, cancer. Conversely, m6A modification, governed by methyltransferases and demethylases, influences mRNA stability, processing, and translation, affecting genes central to autophagic pathways. As we delve deeper into the complexities of autophagy regulation, the importance of these methylation modifications grows more evident. The interplay of 6mA, m6A, and autophagy points to a layered regulatory mechanism, illuminating cellular reactions to a range of conditions. This review delves into the nexus between DNA 6mA and RNA m6A methylation and their influence on autophagy in cancer contexts. By closely examining these epigenetic markers, we underscore their promise as therapeutic avenues, suggesting novel approaches for cancer intervention through autophagy modulation.

Keywords: 6mA methylation; autophagy; cancers; m6A methylation; therapy.

Figure 1

The process of autophagy and its regulation for 6mA methylation, m6A methylation and protein modification. (A) Autophagy is initiated with the formation of ULK1 complex (ULK1-ATG13-FIP200-ATG201) and PI3K complex facilitate the formation of phagophore. ATG5-ATG12-ATG16 complex and PE-conjugated-LC3II promote phagophore elongation and autophagosome formation. Autophagosome fusion with the lysosome results in the degradation of target molecules. (B) Methylation of DNA, methylation of RNA, and protein modification of protein are reported to participate in autophagy regulation (Pho, phosphorylation; Ace, acetylation; Ubi, ubiquitination; Gly, glycosylation).

Figure 2

Methylation and demethylation of 6mA. 6mA methylation is a dynamic and reversible process coordinated by a series of methyltransferases (METTL4, N6AMT1, DDM-1, DAMT, DAMT-1, and MTA1c termed as “6mA writers”), demethylases (ALKBH1, ALKBH4, DMAD, and NMAD-1 termed as “6mA erasers”).

Figure 3

Molecular composition of m6A RNA methylation. M6A methylation is a dynamic and reversible process coordinated by a series of methyltransferases (METTL3/14, WTAP, RBM15/15B, METTL16, KIAA1429, ZC3H13 and termed as “m6A writers”), demethylases (FTO, ALKBH5 and ALKBH3 “m6A erasers”) and identifiers (YTHDF1/2/3, YTHDC1, HNRNPA2B1, HNRNPC, HNRNPG, eIF3, and IGF2BPs, “m6A Readers”).