Cancer chemoprevention may be achieved through induction of phase II detoxifying enzymes, a process mediated by the antioxidant response element (ARE) in the promoter region of these genes. A key transcription factor involved in induction of phase II enzymes is nuclear factor erythoid-2 related factor (Nrf2). Although cellular function of Nrf2-Keap1 pathway in human carcinogenesis has been extensively investigated, majority of these studies focus on the negative regulator Keap1, which is responsible for cytoplasmic retention of the Keap1-Nrf2 complex, thereby preventing Nrf2-mediated gene transcription. Given the critical role of lysine acetylation in regulating diverse cellular pathways, we use clinically relevant histone deacetylase (HDAC) inhibitors to explore novel mechanisms that govern Nrf2/ARE pathway. By a global proteomic survey, we have learned that the HDAC inhibitor, vorinostat, induces lysine acetylation of 73 proteins in MDA-MB-231 human breast cancer cells. These proteins include chromatin-associated proteins, transcriptional factors, transcriptional regulators, chaperone proteins, DNA repair enzymes, structural proteins and kinase mediators. Among these proteins, SQSTM1 is of particular interest as a recent study has confirmed its critical function in activation of the Nrf2/ARE pathway. Our work shows that vorinostat down-regulates Keap1 protein and elevates protein expression of Nrf2 and NQO1. Induction of Nrf2 by vorinostat is mediated through SQSTM1 as depletion of SQSTM1 by siRNA diminishes the effect of vorinostat on Nrf2 and NQO1. These findings suggest that therapeutic HDAC inhibitors may be found to be useful as chemopreventive agents for breast cancer and support work to elucidate the roles of lysine acetylation in the Nrf2/ARE dependent gene transcription as an underlying mechanism. Supported by FAMRI, Department of Defense Era of Hope, and NIH CA88843.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B104.

Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC