Genome-wide Loss-of-Function Screen Reveals an Important Role for the Proteasome on HDAC Inhibitor-Induced Apoptosis
Genome-wide Loss-of-Function Screen Reveals an Important Role for the Proteasome on HDAC Inhibitor-Induced Apoptosis
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DOI：
10.1016/j.ccr.2008.12.001
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发表时间：
2009-01-06
期刊：
影响因子：
50.3
通讯作者：
La Thangue, Nicholas B.
中科院分区：
文献类型：
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作者：
Fotheringham, Susan;Epping, Mirjam T.;La Thangue, Nicholas B.
异常乙酰化与肿瘤发生密切相关，通过靶向组蛋白去乙酰化酶（hdac）来调节乙酰化作为一种可行的治疗策略正日益加快步伐。全基因组功能缺失筛选鉴定出HR23B，它将泛素化的货物蛋白运送到蛋白酶体，是HDAC抑制剂诱导的细胞凋亡的敏感性决定因素。HR23B还控制肿瘤细胞对直接作用于蛋白酶体的药物的敏感性。HR23B水平影响肿瘤细胞对HDAC抑制剂的反应，在皮肤T细胞原位淋巴瘤中发现HR23B水平较高，这种恶性肿瘤对基于HDAC抑制剂的治疗反应良好。这些结果表明，不受调节的蛋白酶体活性有助于HDAC抑制剂的抗癌活性。
Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.