Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 - A novel basis for antileukemia activity of histone deacetylase inhibitors
Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 - A novel basis for antileukemia activity of histone deacetylase inhibitors
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DOI：
10.1074/jbc.c500186200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Bhalla, K
中科院分区：
文献类型：
--
作者：
Bali, P;Pranpat, M;Bhalla, K
异羟肟酸(HAA)类似物组蛋白脱乙酰酶(HDAC)抑制剂(HDI)LAQ824和LBH589可诱导乙酰化，并抑制热休克蛋白(HSP)90的ATP结合和伴侣功能。这促进了人类白血病细胞中促进生长和促进生存的客户蛋白BCR-Abl、突变的Flt-3、c-Raf和AKT的多泛素化和降解。HDAC6是IIB HDAC类的成员。它主要是胞浆内的微管相关的α-微管蛋白脱乙酰酶，也是已知的促进错误折叠的多泛素化蛋白的侵袭性包含的酶。在这里，我们证明了在表达人白血病K562细胞的bcr-abl癌基因中，HDAC6可以与HSP90免疫共沉淀，并且其siRNA下调HDAC6可以诱导HSP90和α-微管蛋白的乙酰化。HDAC6水平的缺失也抑制了HSP90与ATP的结合，减少了HSP90与其客户蛋白(如bcr-Abl)的伴侣结合，并诱导了bcr-Abl的多泛素化和部分耗竭。相反，HDAC6的异位过表达抑制了LAQ824诱导的HSP90和α-微管蛋白的乙酰化，并减少了LAQ824介导的bcr-Abl、AKT和c-Raf的缺失。综上所述，这些发现表明HDAC6也是一种HSP90脱乙酰酶。靶向抑制HDAC6导致HSP90的乙酰化和其伴侣功能的中断，导致多泛素化和包括BCR-Abl在内的促进生长和促进生存的HSP90客户蛋白的耗尽。HDAC6致敏的人白血病细胞对HAA-HDIs和蛋白酶体抑制剂的耗竭。
The hydroxamic acid (HAA) analogue pan-histone deacetylase (HDAC) inhibitors (HDIs) LAQ824 and LBH589 have been shown to induce acetylation and inhibit the ATP binding and chaperone function of heat shock protein (HSP) 90. This promotes the polyubiquitylation and degradation of the pro-growth and pro-survival client proteins Bcr-Abl, mutant FLT-3, c-Raf, and AKT in human leukemia cells. HDAC6 is a member of the class IIB HDACs. It is predominantly cytosolic, microtubule-associated alpha-tubulin deacetylase that is also known to promote aggresome inclusion of the misfolded polyubiquitylated proteins. Here we demonstrate that in the Bcr-abl oncogene expressing human leukemia K562 cells, HDAC6 can be co-immunoprecipitated with HSP90, and the knock-down of HDAC6 by its siRNA induced the acetylation of HSP90 and alpha-tubulin. Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone association of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl. Conversely, the ectopic overexpression of HDAC6 inhibited LAQ824-induced acetylation of HSP90 and alpha-tubulin and reduced LAQ824-mediated depletion of Bcr-Abl, AKT, and c-Raf. Collectively, these findings indicate that HDAC6 is also an HSP90 deacetylase. Targeted inhibition of HDAC6 leads to acetylation of HSP90 and disruption of its chaperone function, resulting in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins including Bcr-Abl. Depletion of HDAC6 sensitized human leukemia cells to HAA-HDIs and proteasome inhibitors.