Abstract B61: Targeting the ATM pathway through histone deacetylase inhibition.

Abstract

Abstract Ataxia telangiectasia mutated (ATM) is a major regulator of DNA double strand break repair. It is a member of the phosphatidyl inositol 3' kinase-related (PIKK) family of serine/threonine kinases, whose activation is promoted by the MRN complex (MRE11, Rad50, NBS1) in the presence of DNA damage. Mutations in ATM lead to increased susceptibility to developing lymphoid and breast cancers. Cells with mutated ATM often demonstrate enhanced chromatin decondensation, increased genomic instability, and greater sensitivity to DNA damaging agents. Interestingly, pharmacological inhibition of histone deacetylases (HDACs) often results in many of these same traits. Inhibitors of histone deacetylases (HDACs) have been demonstrated to potentiate the effects of various DNA damaging therapies through regulation of chromatin structure and down-regulating DNA repair. The contribution of HDAC proteins to DNA repair have yet to be fully understood. Therefore, we examined the effect of HDACs on DNA damage signaling and repair. Treatment of cancer cells with HDAC inhibitors led to a significant decrease in ATM mRNA and protein levels. This caused attenuated induction of the DNA damage response signaling downstream of ATM in the presence of DNA damage. HDAC inhibition led ultimately to reduced DNA repair after therapeutic induction of DNA damage, and decreased overall cell survival. Select depletion of HDAC1 and HDAC2 was sufficient to reduce ATM expression, and potentiate the effects of DNA damaging agents. These results were recapitulated in vivo and demonstrated that pharmacological inhibition of HDACs significantly reduced the activation of the ATM pathway in response to chemotherapeutic induction of DNA damage. Specifically, HDAC inhibition significantly reduced the levels of ATM and down-stream stabilized p53 after treatment of tumors with therapeutic DNA damaging agents. Taken together, these results suggest a contribution of histone deacetylase enzymes in regulating the ATM pathway in response to DNA damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B61.