Abstract 3069: Pleiotropic tumor suppressor role of microRNA-34b in prostate cancer.

Abstract

Abstract CpG island hypermethylation is one of the most common causes of the loss of tumor-suppressor microRNAs (miRNA) in cancers. Here we show that miR-34b is silenced in human prostate cancer (PCa) and the mechanism is through CpG hypermethylation. We provide evidence that miR-34b directly targets methyltransferases (DNMT) and deacetylases (HDACs). We show that miR-34b expression could predict overall survival and recurrence free survival such that patients with high miR-34b levels had longer survival. Further we elucidate the tumor suppressor role of miR-34b using both in vitro and in vivo models. Functionally miR-34b inhibits cell proliferation, colony formation, migration/invasion and triggers G0/G1 cell cycle arrest and apoptosis in cancer cells. The mechanism is partly through the down regulation of AKT pathway as miR-34b directly targets AKT and causes depletion of its downstream genes. Our results show that over-expression of miR-34b caused a decline in the mesenchymal markers Vimentin, ZO1, N-cadherin and Snail whereas there was an increase in E-cadherin expression. Finally we demonstrated the antitumor effect of miR-34b in vivo. MiR-34b caused a dramatic decrease in tumor growth in nude mice compared to cont-miR. These findings offer new insight into the role of miR-34b in the inhibition of prostate cancer through demethylation, active chromatin modification and AKT pathways and may provide a rationale for the development of new strategies targeting epigenetic regulation of miRNAs for the treatment of prostate cancer. Citation Format: Shahana Majid, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Sumit Arora, Inik Chang, Soichiro Yamamura, Yuichiro Tanaka, Takeshi Chiyomaru, Shinichiro Fukuhara, Guoren Deng, Peter R. Carroll, Rajvir Dahiya. Pleiotropic tumor suppressor role of microRNA-34b in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3069. doi:10.1158/1538-7445.AM2013-3069