HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells
HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells
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DOI：
10.1182/blood-2008-03-143644
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Bhalla, Kapil
中科院分区：
文献类型：
--
作者：
Rao, Rekha;Fiskus, Warren;Bhalla, Kapil
组蛋白脱乙酰酶 6 (HDAC6) 是一种热休克蛋白 90 (hsp90) 脱乙酰酶。用泛 HDAC 抑制剂治疗或通过 siRNA 消除 HDAC6 会诱导过度乙酰化并抑制 ATP 结合和 hsp90 的伴侣功能。用 17-allylamino-demothoxy geldanamycin (17-AAG) 处理也会抑制 ATP 结合和 hsp90 的伴侣功能，导致 hsp90 客户蛋白的多泛素化和蛋白酶体降解。在这项研究中，我们确定了 hsp90 过度乙酰化对 17-AAG 的抗 hsp90 和抗白血病活性的影响。 hsp90 的超乙酰化增加了其与 17-AAG 的结合，并增强了 17-AAG 介导的 ATIP 和辅助伴侣 p23 与 hsp90 结合的减弱。值得注意的是，单独使用 17-AAG 处理也减少了 HDAC6 与 hsp90 的结合，并诱导 hsp90 的过度乙酰化。这促进了 HDAC6 的蛋白酶体降解。与单独使用任一药物相比，17-AAG 和 HDAC6 siRNA 联合治疗可诱导更多的 hsp90 伴侣功能抑制以及 BCR-ABL 和 c-Raf 的消耗。此外，17-AAG 和tubacin 联合治疗增加了K562 细胞的存活率以及原发性急性髓系白血病(AML) 和慢性髓系白血病(CML) 样本活力的损失。这些发现表明 HDAC6 是 hsp90 客户蛋白，hsp90 的高度乙酰化增强了 17-AAG 的抗 hsp90 和抗白血病作用。
Histone deacetylase 6 (HDAC6) is a heat shock protein 90 (hsp90) deacetylase. Treatment with pan-HDAC inhibitors or depletion of HDAC6 by siRNA induces hyperacetylation and inhibits ATP binding and chaperone function of hsp90. Treatment with 17-allylamino-demothoxy geldanamycin (17-AAG) also inhibits ATP binding and chaperone function of hsp90, resulting in polyubiquitylation and proteasomal degradation of hsp90 client proteins. In this study, we determined the effect of hsp90 hyperacetylation on the anti-hsp90 and antileukemia activity of 17-AAG. Hyperacetylation of hsp90 increased its binding to 17-AAG, as well as enhanced 17-AAG-mediated attenuation of ATIP and the cochaperone p23 binding to hsp90. Notably, treatment with 17-AAG alone also reduced HDAC6 binding to hsp90 and induced hyperacetylation of hsp90. This promoted the proteasomal degradation of HDAC6. Cotreatment with 17-AAG and siRNA to HDAC6 induced more inhibition of hsp90 chaperone function and depletion of BCR-ABL and c-Raf than treatment with either agent alone. In addition, cotreatment with 17-AAG and tubacin augmented the loss of survival of K562 cells and viability of primary acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) samples. These findings demonstrate that HDAC6 is an hsp90 client protein and hyperacetylation of hsp90 augments the anti-hsp90 and anti-leukemia effects of 17-AAG.