INHIBITION OF HISTONE DEACETYLASE 6 ACETYLATES AND DISRUPTS THE CHAPERONE FUNCTION OF HEAT SHOCK PROTEIN 90: A NOVEL BASIS OF 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 OF ANTILEUKEMIA ACTIVITY OF HISTONE DEACETYLASE INHIBITORS
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发表时间：
2005
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通讯作者：
P. Bali;M. Pranpat;J. Bradner;M. Balasis;W. Fiskus;F. Guo;K. Rocha;S. Kumaraswamy;S. Boyapalle-S.-Boyapall
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作者：
P. Bali;M. Pranpat;J. Bradner;M. Balasis;W. Fiskus;F. Guo;K. Rocha;S. Kumaraswamy;S. Boyapalle-S.-Boyapall
异羟肟酸（HAA）类似物泛组蛋白脱乙酰酶（HDAC）抑制剂（HDIs）LAQ 824和LBH 589已显示诱导乙酰化并抑制热休克蛋白（hsp）90的ATP结合和伴侣功能。这促进了人白血病细胞中促生长和促存活客户蛋白Bcr-Abl、突变体FLT-3、c-Raf和AKT的多聚泛素化和降解。HDAC 6是HDAC的IIB类成员。它主要是胞质、微管相关的α -微管蛋白脱乙酰酶，也已知其促进错误折叠的多聚泛素化蛋白质的聚集体包含。在表达Bcr-Abl癌基因的K562细胞中，HDAC 6可与hsp 90共沉淀，K562载体对照细胞与抗Abl抗体共沉淀，免疫沉淀物为抗hsp 90或抗Abl抗体。D，将来自表达HDAC 6 siRNA的K562细胞或来自未处理或LAQ 824处理的K562对照细胞的细胞裂解物用对照小鼠IgG或抗Abl抗体免疫沉淀，并将免疫沉淀物用抗泛素或抗Abl抗体免疫印迹。或者，用抗Abl、AKT或抗c-Raf抗体对细胞裂解物进行免疫印迹。β -肌动蛋白的水平用作上样对照。E，用5 nM硼替佐米、250 nM LAQ 824或硼替佐米和LAQ 824的组合处理表达HDAC 6 siRNA的K562细胞或K562对照细胞48小时。随后，通过台盼蓝排除法测定细胞的活力。每次处理后非活细胞的平均百分比值（三次实验）表示为条形图。
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 of HDACs. It is predominantly cytosolic, microtubule associated, α -tubulin deacetylase, which 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, K562 vector control cells were immunoprecipitated with anti-Abl antibody, and the immunoprecipitates were either immunoblotted anti-hsp90 or anti-Abl antibody. D, The cell lysates from K562 cells expressing HDAC6 siRNA or from untreated or LAQ824-treated K562 control cells were immunoprecipitated with either with the control mouse IgG or anti-Abl antibody, and the immunoprecipitates were either immunoblotted with anti-ubiquitin or anti-Abl antibody. Alternatively, the cell lysates were immunoblotted with anti-Abl, AKT or anti-c-Raf antibody. The levels of β -actin served as the loading control. E, K562 cells expressing HDAC6 siRNA or K562 control cells were treated with 5 nM bortezomib, 250 nM LAQ824 or a combination of bortezomib and LAQ824 for 48 hours. Following this, the viability of cells was determined by trypan blue exclusion method. The mean percentage values (of three experiments) for non-viable cells following each treatment are represented as bar graphs.