Histone Deacetylase Hdac Inhibitors In Recent Clinical Trials For Cancer Therapy PDF Download

Abstract: Histone deacetylase (HDAC) is recognized as one of the promising targets for cancer therapy as aberrant transcriptional regulation of the epigenetic system has been linked to tumorigenesis. To date, many HDAC inhibitors have entered clinical trials in light of their high potency in inhibiting tumor cell growth without incurring significant toxicity. Although the effects of HDAC inhibitors on chromatin remodeling and transcriptional regulation are well understood, an increasing body of evidence suggests that modulation of gene expression might not be exclusively responsible for the antineoplastic effects of these agents. In the first part of this study, we demonstrate a novel histone acetylation-independent mechanism by which HDAC inhibitor induces Akt dephosphorylation in U87MG glioblastoma cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This selective histone acetylation-independent action of HDAC inhibitors on HDAC-PP1 complexes also represents the first example of modulating specific PP1 interactions by small-molecule agents. The results of the second part of this study present the efficacy of (S)-HDAC-42, a novel HDAC inhibitor synthesized in our laboratory, in prostate cancer cells. We demonstrate that the antitumor effects of (S)-HDAC-42 are attributed to both histone acetylation-dependent and -independent mechanisms by interfering with the activation or expression status of a number of signaling targets. Together, these mechanisms provide a molecular basis to account for the efficacy of (S)-HDAC-42 in suppressing established prostate xenograft tumor growth. The third part of this study reports another transcriptional regulation-independent anticancer effect of HDAC inhibitor; the inhibition of DNA damage repair. We show that pretreatment of the Bax-deficient DU-145 cells with HDAC inhibitors increased Ku70 acetylation, thereby reducing Ku70's DNA end-binding affinity and diminishing the cellular capability to repair DNA damage. The ability of HDAC inhibitors to modify DNA damage repair underlies the viability of their combination with DNA damaging agents as a therapeutic strategy for prostate cancer. This dissertation research characterizes two novel histone acetylation-/transcriptional regulation-independent anticancer effects of HDAC inhibitors. Moreover, we also show that these histone acetylation-dependent and -independent mechanisms underscore the pleiotropic antineoplastic effects of HDAC inhibitors at both epigenetic and cellular levels.