Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells
Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells
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泛素 B：曲古抑菌素 A 诱导的人类癌细胞肿瘤选择性杀伤的重要介质
DOI：
10.1038/cdd.2009.142
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Zhou, J.
中科院分区：
文献类型：
--
作者：
Wu, P.;Tian, Y.;Zhou, J.
虽然组蛋白去乙酰化酶抑制剂（HDACi）正在成为一类新的抗癌剂，但HDACi选择性杀伤肿瘤的机制还不清楚。我们利用反义拯救技术（SMART）来筛选负责肿瘤选择性杀伤的关键基因。共鉴定出24个基因，其中最重要的是泛素B（Ub B）。TSA可选择性上调肿瘤细胞中UbB的表达，但对非恶性肿瘤细胞无明显影响。进一步观察表明，TSA诱导HeLa细胞线粒体跨膜电位的大量耗散，细胞色素c释放到胞质溶胶中，以及caspase-3/9的蛋白水解切割，这显然是通过泛素化和随后的线粒体膜蛋白包括BCL-2和MCL-1的降解介导的。与此相反，UbB表达的敲低抑制TSA诱导的凋亡级联反应，通过废除TSA诱导的泛素化和随后的线粒体膜蛋白降解。此外，另一HDACi阿匹西定（apicidine）表现出与TSA相似的活性。有趣的是，TSA诱导K562白血病细胞中BCR-ABL融合蛋白的UbB依赖性蛋白酶体降解。因此，我们的研究结果强调了UbB和UbB依赖性蛋白酶体蛋白降解在HDACi诱导的肿瘤选择性中的重要作用。该机制为剖析HDACi的肿瘤选择性的分子机制提供了一个新的起点。
Although histone deacetylase inhibitors (HDACis) are emerging as a new class of anticancer agents, the mechanism of tumor-selective killing by HDACi is not well understood. We used suppression of mortality by antisense rescue technique (SMART) to screen the key genes responsible for the tumor-selective killing by trichostatin A (TSA). Twenty-four genes were identified, the most significant of which was ubiquitin B (UbB). The expression of UbB was selectively upregulated by TSA in tumor cells, but not non-malignant cells. Further observation indicated that TSA induced a substantial dissipation of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, and proteolytic cleavage of caspases-3/9 in HeLa cells, which was apparently mediated by ubiquitylation and the subsequent degradation of mitochondrial membrane proteins including BCL-2 and MCL-1. In contrast, knockdown of UbB expression inhibited the TSA-induced apoptotic cascade by abolishing TSA-induced ubiquitylation and the subsequent degradation of mitochondrial membrane proteins. Furthermore, apicidine, another HDACi, exhibited activity similar to that of TSA. Interestingly, TSA induced UbB-dependent proteasomal degradation of BCR–ABL fusion protein in K562 leukemic cells. Thus, our findings highlight the essential role of UbB and UbB-dependent proteasomal protein degradation in HDACi-induced tumor selectivity. The mechanism provides a novel starting point for dissecting the molecular mechanism underlying the tumor selectivity of HDACi.