Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis
Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis
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USP7 稳定组蛋白去甲基化酶 PHF8 可促进乳腺癌发生。
DOI：
10.1172/jci85747
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发表时间：
2016-06-01
影响因子：
15.9
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Wang, Qian;Ma, Shuai;Shi, Lei
组蛋白去甲基化酶PHF8与多种病理性疾病有关，包括X连锁精神发育迟滞和肿瘤发生。然而，目前尚不清楚PHF8的丰度和功能是如何调节的。在这里，我们报告说，PHF8物理协会与去泛素化酶USP7。具体来说，我们证明USP 7促进PHF 8的去遍在蛋白化和稳定化，导致一组基因（包括细胞周期蛋白A2）的上调，这些基因对细胞生长和增殖至关重要。USP7编码基因也通过正反馈由PHF8转录调控。USP7在乳腺癌组织中呈高表达，其表达水平与PHF 8、cyclin A2的表达及乳腺癌的组织学分级呈正相关。我们发现USP7通过稳定PHF 8和上调细胞周期蛋白A2促进乳腺癌的发生，并且在DNA损伤期间USP7和PHF 8之间的相互作用增强。此外，USP7促进的PHF8稳定赋予细胞对遗传毒性损伤的抗性，并且是BLM和KU70的募集所必需的，这两者对于DNA双链断裂修复都是必不可少的。我们的研究从机械上将USP 7与表观遗传调节和DNA修复联系起来。此外，这些数据支持将USP 7和PHF 8作为乳腺癌干预的潜在靶点，特别是与化疗或放疗联合使用。
The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.