A HDAC6-selective inhibitor is a promising new therapeutic agent for cancer treatment, but its precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDAC6 inhibitor-induced effects has not been fully elucidated. Here, we show that a γ-lactam based HDAC inhibitor A452 selectively inhibits HDAC6 catalytic activity in vivo and in vitro. A452 causes cell death as well as growth inhibition of transformed cells not observed in normal cells. A452 exhibits differential cytotoxicity for wild-type (wt) and mutant p53 (mutp53) human colorectal cancer cells. Interestingly, A452 shows different mechanisms of action of modulating p53 in cancer cells. A452 increases wtp53 by destabilizing MDM2 and MDMX. In contrast, A452 causes mutp53 destabilization by inhibiting complex formation between Hsp90 and hyperstable mutp53, which is a hallmark of p53 mutation and cancer cell-specific. A452 also chemosensitizes cancer cells differing in p53 status for chemotherapy due to its ability to degrade mutp53 and stabilize wtp53. Intriguingly, acetylation of Hsp90 by A452 results in its degradation as well as inactivation of its chaperone activity. Furthermore, A452 effectively suppresses cell migration and invasion. These results demonstrate that A452 is a specific HDAC6 inhibitor and requires for p53 and Hsp90 for inducing anticancer action. Therefore, these results suggest that therapeutic targeting of HDAC6 may represent a new way to treat cancers expressing mutant forms of p53.

Citation Format: So Hee Kwon. Selective Inhibition of HDAC6 regulates preferential cytotoxicity in cancer cells by modulating p53 and Hsp90 stability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5324. doi:10.1158/1538-7445.AM2015-5324

©2015 American Association for Cancer Research.
2015