Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer with a very low survival rate and limited treatment options. Aberrant expression of MYC oncogene plays a crucial role in the progression of PDAC. Recent reports have established the significance of enhancer RNAs (eRNAs), originated from active enhancer or super-enhancer regions, in controlling gene transcription. Our study has identified how novel MYC eRNAs regulate MYC gene expression during chronic inflammatory condition in pancreatic cells. The higher amount of MYC eRNA has been observed in chronic pancreatitis and in pancreatic cancer patients as well. We have shown that MYC-490 kb eRNA interacts with YEATS2, a histone reader protein of ATAC-HAT complex and augments the association of YEATS2-containing ATAC complex to MYC promoter/enhancer region and thus increases MYC gene expression. A TNF-α induced Tyrosine dephosphorylation cycle regulates the MYC eRNA binding to YEATS2 protein in cancer cell. Thus, our study has added another layer of MYC gene expression regulation by enhancer-driven transcripts which can be used as a potential therapeutic target for treating pancreatic cancer.