Abstract 3417: Class III HDAC induces epithelial-to-mesenchymal transition in prostate cancer cells

Abstract

Abstract The epithelial-to-mesenchymal transition (EMT) is a crucial program for initiating invasion and metastasis in many epithelial tumors. EMT is characterized by loss of cell adhesion and increased cell mobility; however, the mechanism underlying this transition is not fully understood. Here we identified SIRT1, a class III histone deacetylase, as a critical regulator of EMT. We show that forced expression of SIRT1 disrupts the epithelial morphology in non-transformed prostate epithelial cells, concomitant with a decrease of epithelial marker E-cadherin, and an increase of mesenchymal protein N-cadherin, and fibronection expression, indicating EMT. In contrast, silencing SIRT1 expression in metastatic prostate tumor cells restores cell to cell adhesion and induces changes in morphology characteristic of epithelial cells, concomitant with an increase of E-cadherin and a decrease of N-cadherin and fibronection expressions. In addition, we show that SIRT1 represses the activity of the E-cadherin proximal promoter with an E-box dependent mechanism, indicating a connection between SIRT1 and the zinc-finger EMT transcription factor, which needs the E-box to suppress E-cadherin transcription. Moreover, we performed ChIP assays to show that SIRT1 and ZEB1 bind to the same DNA fragment on the E-cadherin promoter, and SIRT1 occupancy in the E-cadherin promoter requires ZEB1. In addition, we show that acetylated H3K9 levels were inversely related to occupancy of SIRT1 and ZEB1. Finally, our results show that SIRT1 knockdown reduces prostate cancer cell migration and invasion. Thus, in this study we identified SIRT1 as an important regulator of EMT and demonstrated a new transcriptional mechanism regulating E-cadherin expression by the cooperation of SIRT1 with ZEB1. These findings suggest that overexpressed SIRT1 in prostate cancer cells may be targeted to reverse EMT, and SIRT1 could be a potential target in the treatment of prostate cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2011-3417