Abstract 1913: Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations

Abstract

Abstract Identification of epigenetic reversal agents for use in combination chemotherapies for human pancreatic ductal adenocarcinomas remains an unmet clinical need. Pharmacological inhibitors of EZH2 are emerging as potential epigenetic reversal agents in various solid tumors and leukemia, however, the surprisingly small set of mRNA transcripts identified with EZH2 knockdown suggests novel mechanisms to govern their anti-tumorigenic effects. Here, we report 3-deazaneplanocin-A, an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, to significantly reprogram the noncoding miRNA expression, including a subset of PDAC-downregulated miRNAs, to dampen TGF-β-induced EMT signals in pancreatic cancer. Particularly, we identify epigenetic silencing of miR-663a and -4787-5p in PDAC tissues and cell lines that are reactivated by 3-deazaneplanocin-A to directly target TGF-β1 for RNA interference. Lentiviral overexpression of miR-663a and -4787-5p partially phenocopied 3-deazaneplanocin-A's EMT resisting effects in pancreatic cancer cells, whereas locked nucleic acid antimiR-663a and -4787-5p mitigated them. In vivo, 3-deazaneplanocin-A, miR-663a and -4787-5p significantly reduced tumor burden and metastasis in an orthotopic mouse pancreatic tumor model with miR-663a displaying more potency than miR-4787-5p in curtailing TGF-β1 signaling pathway. These findings reveal tumor miRNA reprogramming as a novel approach for controlling TGF-β-induced EMT in human PDAC and uncover a list of putative miRNA targets that may guide further selection and development of synthetic histone methylation reversal agents for clinical use. Citation Format: Rajgopal Govindarajan, Hardik Modi. Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1913.