Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma
Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma
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DOI：
10.1182/blood-2009-07-235663
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发表时间：
2010-07-22
期刊：
影响因子：
20.3
通讯作者：
Furukawa, Yusuke
中科院分区：
文献类型：
--
作者：
Kikuchi, Jiro;Wada, Taeko;Furukawa, Yusuke
硼替佐米现在被广泛用于治疗多发性骨髓瘤（MM）;然而，其作用机制尚未完全了解。尽管有初步结果，但最近的研究表明硼替佐米不会抑制MM细胞中的核因子-κ B活性，这表明存在导致细胞毒性的其他关键途径。在这项研究中，我们发现组蛋白脱乙酰酶（HDAC）是硼替佐米的关键靶点，硼替佐米在转录水平特异性下调MM细胞系和原代MM细胞中I类HDAC（HDAC 1，HDAC 2和HDAC 3）的表达，伴随着相互的组蛋白超乙酰化。HDAC的转录抑制是由Sp1蛋白的caspase-8依赖性降解介导的，Sp1蛋白是I类HDAC基因的最有效的反式激活因子。短干扰RNA介导的HDAC 1敲低增强硼替佐米诱导的细胞凋亡和组蛋白高乙酰化，而HDAC 1过表达抑制它们。HDAC 1过表达赋予MM细胞对硼替佐米的抗性，并且给予HDAC抑制剂罗米地辛在体外和体内恢复HDAC 1过表达细胞对硼替佐米的敏感性。这些结果表明硼替佐米通过与常规HDAC抑制剂不同的机制靶向HDAC。我们的研究结果为硼替佐米在MM治疗中的应用提供了新的分子基础和理论依据。（血。2010; 116（3）：406-417）
Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-kappa B activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8-dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment. (Blood. 2010; 116(3): 406-417)