The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2
The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2
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DOI：
10.1093/emboj/cdg315
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发表时间：
2003-07-01
期刊：
影响因子：
11.4
通讯作者：
Göttlicher, M
中科院分区：
文献类型：
--
作者：
Krämer, OH;Zhu, P;Göttlicher, M
组蛋白修饰酶在生理和异常基因调控中起重要作用。由于组蛋白去乙酰化酶（HDAC）是癌症治疗的有希望的靶点，因此了解HDAC调控机制是重要的。HDAC同工酶的选择性调节剂可以作为有效和耐受性良好的药物。我们表明，HDAC 2通过泛素-蛋白酶体途径进行基础营业额。丙戊酸（VPA）除了选择性抑制I类HDAC的催化活性外，还诱导HDAC 2的蛋白酶体降解，这与其他抑制剂（如阿司他汀A（TSA））相反。基础和VPA诱导的HDAC 2周转主要依赖于E2泛素缀合酶Ubc 8和E3泛素连接酶RLIM。Ubc 8基因表达由VPA和TSA诱导，而只有TSA同时降低RLIM蛋白水平，因此不能诱导HDAC 2降解。因此，多聚泛素化和蛋白酶体降解为HDAC 2的下调提供了同工酶选择性机制。
Histone-modifying enzymes play essential roles in physiological and aberrant gene regulation. Since histone deacetylases (HDACs) are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. Selective modulators of HDAC isoenzymes could serve as efficient and well-tolerated drugs. We show that HDAC2 undergoes basal turnover by the ubiquitin-proteasome pathway. Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as trichostatin A (TSA). Basal and VPA-induced HDAC2 turnover critically depend on the E2 ubiquitin conjugase Ubc8 and the E3 ubiquitin ligase RLIM. Ubc8 gene expression is induced by both VPA and TSA, whereas only TSA simultaneously reduces RLIM protein levels and therefore fails to induce HDAC2 degradation. Thus, poly-ubiquitination and proteasomal degradation provide an isoenzyme-selective mechanism for downregulation of HDAC2.