Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p.
The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic 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, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding microRNA (miRNA) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRNAs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep's EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRNAs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo 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 TGFβ1-induced EMT features in human PDAC and uncover putative miRNA targets involved in the process.



The findings support the potential for synthetic histone methylation reversal agents to be included in future epigenetic-chemotherapeutic combination therapies for pancreatic cancer. Mol Cancer Res; 14(11); 1124-35. ©2016 AACR.
Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio.|Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
Hardik R
HR
Mody
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
Sau Wai
SW
Hung
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
Mohammad
M
AlSaggar
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
Jazmine
J
Griffin
The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. govindarajan.21@osu.edu.|Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio.|Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
Rajgopal
R
Govindarajan
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006657:Histones; C552243:MIRN663 microRNA, human; D035683:MicroRNAs; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C048460:3-deazaneplanocin; D008780:Methyltransferases; C434266:S-adenosyl-L-methionine-dependent N-methyltransferase; D000241:Adenosine