Chromatin (DNA & Histone) modifications regulates gene expression/repression and termed in molecular level as “epigenetics”. Tumor development and cancer progression follow, in part, the developmental proceedings. Autophagy is an evolutionarily conserved catabolic process, which cells execute in stress conditions for their survival or to commit suicide. The genes of the respective protein components of autophagy associated with the process of induction of autophagy, autophagosome formation, fusion of autophagosome with lysosome and degradation of cytoplasmic components should have their specific regulatory mechanisms, which would be the molecular connection between epigenetics and autophagy. DNA methylation at cytosine 5-carbon position (hereafter, DNA methylation) by DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) repress genes when their promoters CpG islands are hypermethylated. Silencing of tumor suppressor genes and induction of oncogenes induce development of tumor and progression of cancer. 5-aza-2'-deoxycytidine (AzaC) is frequently use to re-express the silenced genes as inhibitor of DNMTs. Mechanistically, AzaC is incorporated to daughter DNA strands in each cycle of division, DNA methylation at the respective sites follow replication. If AzaC occupy the respective cytosine spot – DNMT1 could not complete the methylation. Although I am working on epigenetics of cancer for the last 25 years, only recently, we have deciphered that AzaC treatment to lung and breast cancer cells enhance expression of some genes and repress some other genes, including DNMT1. At a moderately high concentration of AzaC treatment cell adopt survival strategy through autophagy against the genotoxic stress imposed by AzaC. In this scenario, I shall present our data, how cells cope up with DNA-methylation epigenetic stress through autophagy by high expression of histone modification epigenetic eraser/enzyme, histone deacetylase and DNMT1-specific miRNAs.
Niharika et al. (2025) DNMT1-inhibition by synergistic application of curcumin and 5-AZA-2'-deoxycytidine implicates enhanced therapeutic potential against lung adenocarcinoma. Comput Biol Med. 196(Pt B):110763.