Histone deacetylase 3 as a novel therapeutic target in multiple myeloma.
Histone deacetylase 3 as a novel therapeutic target in multiple myeloma.
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作者：
组蛋白脱乙酰酶（HDAC）代表用于治疗各种类型的癌症（包括多发性骨髓瘤（MM））的新型分子靶标。许多HDAC抑制剂已经在临床前环境中显示出显著的抗肿瘤活性;然而，由于与其广泛的HDAC抑制作用相关的不利毒性，它们的临床用途受到限制。异构体选择性HDAC抑制可以允许MM细胞毒性而没有伴随的副作用。在这项研究中，我们证明了HDAC 3敲低和小分子HDAC 3抑制剂BG 45通过凋亡触发显著的MM细胞生长抑制，这通过胱天蛋白酶和PARP切割得到证明。重要的是，HDAC 3抑制下调STAT 3的磷酸化（酪氨酸705和丝氨酸727）。IL-6和骨髓基质细胞都不能克服HDAC 3抑制对p-STAT 3和MM细胞生长的这种抑制作用。此外，HDAC 3抑制还触发STAT 3的超乙酰化，表明STAT 3的磷酸化和乙酰化之间的串扰信号传导。重要的是，抑制HDAC 3（而不是HDAC 1或HDAC 2）会显着增强硼替唑米诱导的细胞毒性。最后，我们证实，单独和与硼替佐米组合的BG 45在人MM的鼠异种移植模型中在体内触发显著的肿瘤生长抑制。我们的结果表明，HDAC 3代表了一个有前途的治疗靶点，并验证了MM中原型新型HDAC 3抑制剂BG 45。
Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and PARP cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of STAT3. Neither IL-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on p-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or HDAC2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.
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影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
DOI：
10.1158/1078-0432.ccr-08-2787
发表时间：
2009-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Schrump DS
通讯作者：
Schrump DS
影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
20.3
作者：
Mitsiades, N;Mitsiades, CS;Anderson, KC
通讯作者：
Anderson, KC
DOI：
10.1083/jcb.200812060
发表时间：
2009-06-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee JL;Wang MJ;Chen JY
通讯作者：
Chen JY