Abstract CN12-02: Dietary HDAC inhibitors: Prevention or therapy?
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AbstractLysine deacetylase inhibitors, which include inhibitors of histone deacetylase (HDAC) enzymes, are undergoing clinical trials as anticancer agents. Some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno--keto metabolite of the dietary compound methylselenocysteine triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2 modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with STAT3/Sp3 transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor, or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first study to identify a direct target gene of HDAC8 repression, namely BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors and their roles as chemopreventive vs. therapeutic agents. Supported by NIH P01 grant CA090890.Citation Format: Roderick H. Dashwood. Dietary HDAC inhibitors: Prevention or therapy? [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN12-02.
