Abstract 4033: Epigenetic alterations in the multifaceted inhibitory effects of metformin on castration resistant prostate cancer

Abstract

Abstract We recently demonstrated that metformin reduced MYC oncogene protein levels both in vitro and in vivo to inhibit prostate cancer (PCa) growth. MYC oncogene, known for its critical role in prostate carcinogenesis, interacts and recruits protein complexes with histone acetylases activities on the bound targets indicating epigenetic alterations are associated with MYC function. The importance of epigenetic events in PCa growth include facilitation of androgen receptor (AR) signaling and stabilizing AR in PCa cells by histone-modifying enzymes. The conversion of early stage tumors into invasive malignancies with an aggressive phenotype associated with the irreversible loss of epithelial markers from hyper-methylation. We hypothesize that metformin reduces the growth and migration of castration resistant prostate cancer (CRPC) via epigenetic alterations. We demonstrated that metformin inhibits cellular proliferation of the castration resistant cell lines, human C4-2b PCa and Myc-CaP mouse PCa cells. In vivo, metformin reduced the incidence of prostatic intraepithelial neoplasia lesion development in Hi-Myc mice after 4-week-treatment and further reduced PCa incidence after 24-week-treatment. Metformin also reduced tumor growth in subcutaneous xenograft model with C4-2b cells in athymic mice after 4-week treatment. The reduction of CRPC cell growth was resulted from a combined force from metformin induced cell cycle arrest at G1 phase, stimulation of apoptosis and autophagy. Western blots and IHC analysis were performed to demonstrate that metformin inhibition of PCa growth is associated with reduced AR expression in vitro and in vivo. The expression of a methyltransferase Suv39H1, which was recently identified to regulated PCa growth, migration and AR activation, was significantly suppressed by metformin at mRNA and protein levels in CRPC cells. Metformin also reduced the interaction between Suv39H1 and class III deacetylase Sirt1 in CRPC cells. Suv39H1 and Sirt1 could regulate the levels of the H3K9 methylation of the target genes, which is strongly associated with regional variation in chromatin organization and mutation rate variation in somatic cells. As expected with the reduction of Suv39H1 expression and activity to stimulate H3K9 methylation, cell migration and mobility was suppressed in metformin treated CRPC cells. Our data indicate that metformin altered epigenetic enzymes, Suv39H1 and Sirt1, to down-regulate AR expression and activity, cell growth and migration. Taken together, this study revealed a novel molecular mechanism through Suv39H1 and Sirt1 to mediate the multifaceted inhibitory effects of metformin against CRPC including the stimulation of cell cycle arrest, apoptosis, autophagy and migration. Citation Format: Xin Li, Juncheng Wei, Satoko Matsumura, Yuqi Guo, Huawei Yuan. Epigenetic alterations in the multifaceted inhibitory effects of metformin on castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2014-4033