Arsenic Trioxide Exerts Antimyeloma Effects by Inhibiting Activity in the Cytoplasmic Substrates of Histone Deacetylase 6

• DOI: 10.1371/journal.pone.0032215
• Publication Date: 2012-02-22T22:12:48Z
• Authors: Xiaoyan Qu; Juan Du; Chunyang Zhang; Weijun Fu; Hao Xi; Jianfeng Zou; Jian Hou
• Keywords: Arsenic Trioxide; HDAC6; HDAC10

Arsenic trioxide (As2O3) has shown remarkable efficacy for the treatment of multiple myeloma (MM). Histone deacetylases (HDAC) play an important role in control gene expression, and their dysregulation been linked to myeloma. Especially, HDAC6, a unique cytoplasmic member class II, which mainly functions as α-tubulin deacetylase Hsp90 deacetylase, become target drug development treat cancer due its major contribution oncogenic cell transformation. However, mechanisms action As2O3 have not yet defined. In this study, we investigated effect on proliferation apoptosis human line primary cells, then studied that exerts antimyeloma effects by inhibiting activity through western blot analysis immunoprecipitation. We found acts directly MM cells at relatively low concentrations 0.5∼2.5 µM, survival cells. inhibited HDAC high concentration dose-dependent manner (great than 4 µM). Subsequently, dose- time-dependent fashion markedly increased level acetylated Hsp90, chaperone association with IKKα activities degradation IKKα. Importantly, loss IKKα-associated occurred prior any detectable levels IKKα, indicating novel pathway down-regulates HDAC6 destabilize protein via function. Furthermore, observed TNF-α-induced NF-κB signaling was significantly reduced phosphorylation Ser-536 p65. Therefore, our studies provide insight into molecular mechanism anti-myeloma HDAC6-Hsp90-IKKα-NFκB axis rationale can be extended readily using all associated diseases.