A Novel Target of Histone Deacetylase Inhibitor, Involves in Mitochondria Membrane Protein Ubiquitination and Regulates Apoptosis.

Inhibitors of histone deacetylases (HDACIs) are a new generation of anticancer agents that selectively kill tumor cells. However, the molecular basis for their tumor selectivity is not well understood. we employed a genetic technique, named suppression of mortality by antisense rescue technique(SMART), to understand the molecular mechanism of apoptosis induced by HDACI and identify the genes that participate in this process. We identified several novel genes and demonstrated that HDACIs promote apoptosis through activation ubiquitin/proteasome by inducing ubiquitin B not ubiquitin C gene expression. According to degrading the mitochondria membrane protein Mcl-1 by activated ubiquitin/proteasome system, the mitochondria potential collapse and cell apoptosis. Further observation demonstrated that depletion of MCL-1 by RNA interference (RNAi) sensitizes Hela cells to TSA mediated mitochondria membrane potential collapse and apoptosis, and overexpression of MCL-1 confers apoptosis resistance.