POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation.
POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation.
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POH1 去泛素化并稳定 E2F1 以促进肿瘤形成
DOI：
10.1038/ncomms9704
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发表时间：
2015-10-29
影响因子：
16.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wang B;Ma A;Zhang L;Jin WL;Qian Y;Xu G;Qiu B;Yang Z;Liu Y;Xia Q;Liu Y
转录因子E2 F1的过度激活经常发生在人类癌症中，并导致恶性进展。E2 F1活性受泛素-蛋白酶体系统介导的蛋白水解调节。然而，控制E2 F1泛素化和稳定性的去泛素化酶仍然不确定。在这里，我们证明了去泛素化酶POH 1通过结合和去泛素化E2 F1来稳定E2 F1蛋白。Poh 1等位基因的条件性敲除导致原代小鼠肝细胞中E2 F1表达降低。POH 1介导的E2 F1表达调节增强了E2 F1下游促生存信号，包括Survivin和FOXM 1蛋白水平的上调，并有效地促进了裸鼠中肝癌细胞的肿瘤生长。重要的是，人肝细胞癌（HCC）重演了POH 1对E2 F1表达的调节，因为HCC中POH 1的核丰度增加，并与E2 F1过表达和肿瘤生长相关。因此，我们的研究表明，过度激活的POH 1-E2 F1调节可能有助于肝癌的发展。 转录因子E2 F1控制多个基因的表达，并且在癌症中经常过度激活。在这里，作者表明E2 F1被POH 1去遍在蛋白化，这增强了E2 F1在细胞存活中的作用，并有助于肝癌的发病机制。
Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin–proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1–E2F1 regulation may contribute to the development of liver cancer. The transcription factor E2F1 controls the expression of multiple genes and is frequently overactivated in cancer. Here, the authors show that E2F1 is deubiquitinated by POH1 and that this enhances the role of E2F1 in cell survival, and contributes to the pathogenesis of liver cancer.