Taken DNA methylation and mRNA together to reveals genes associated with cisplatin resistance in NSC

Epigenetics is known as the regulation of gene expression without changes to DNA sequence. Developments in the field of molecular biology have uncovered a new layer of complexity lying beyond classical epigenetic mechanisms, such as methylation of DNA or posttranslational modification of histones. The vast majority of the human genome is transcribed, but that only around 2% of these transcripts are translated into protein.

Short ncRNAs have been extensively classified based on their genomic origins and precise mechanisms of action. The microRNAs (miRNAs), which are 20-23 nucleotides (nts) in length and usually recognize target mRNAs by complementarity to a 2-7 nt long seed region in the 3'-UTR. During fertilization and implantation of embryos, DNA demethylation and subsequent re-methylation occurs and that DNA methyltransferases (DNMTs) 1-3 propagate CpG methylation after S-phase across mitoses by associating with hemimethylated DNA genomic loci producing non-coding transcripts.

Studies clarifying the link between environmental stimuli and changes in ncRNA function are crucial for a more complete understanding of the role of these transcripts.

Just like the modified version of Francis Crick’s "central dogma," in which RNA is not only a stop on the journey between DNA and protein, but provides important regulatory feedback, influencing both transcription and translation. We can believe that transcripts targeted by these mechanisms work as epigenetic intermediaries and spreading the message though a vast network of dynamic regulation of gene expression.

Non-small cell lung cancer (Nsclc) accounts for almost 85% of overall lung cancers. Cisplatin (DDP) is widely used in the standard chemotherapy treatment for NSCLC. The response to chemotherapy differs among cancer patients, and the efficacy of DDP treatment is often diminished by resistance to the drug. DNA methylation at CpG islands within or near promoter regions has been proved as an important epigenetic regulatory mechanism of gene expression. Hypermethylation could lead to a change of the chromatin framework, directly repressing transcription and leading to the downregulation or silencing of tumor suppressor genes, thus helping to cancer initiation and progression.

Recently, Researchers use gene expression and methylation profiling to identify candidate DNA methylation drivers of DDP resistance in NSCLC. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo.

This work identified a panel of candidate genes down regulated by DNA methylation and demonstrated that these genes induced DDP resistance. Epigenetic therapy reactivated cells to DDP both in vitro and in vivo. And, proved that overexpression of GAS1 directly affected the DDP chemosensitivity of resistant cells. All of those evidences enhanced the understanding of DDP resistance mechanisms and contributed to developments for treatment for NSCLC.