Rajgopal Govindarajan
Ohio State University, USA
Title: Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGF- β1-induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p
Biography
Biography: Rajgopal Govindarajan
Abstract
Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of enhancer of zeste homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms that contribute to their anti-tumorigenic effects. Here we report 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, to significantly reprogram noncoding miRNA expression and dampen TGF-β1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, we identify miR- 663a and miR-4787-5p as PDAC-downregulated miRNAs that are reactivated by DZNep to directly target TGF-β1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGF-β1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. In vivo, DZNep, miR-663a, and miR-4787-5p reduced tumor burden and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRNAs by synthetic histone methylation reversal agents as a viable approach to attenuate TGF-β1-induced EMT features in human PDAC and uncover putative miRNA targets involved in the process.