USP9X regulates centrosome duplication and promotes breast carcinogenesis.
USP9X regulates centrosome duplication and promotes breast carcinogenesis.
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USP9X 调节中心体复制并促进乳腺癌发生
DOI：
10.1038/ncomms14866
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发表时间：
2017-03-31
影响因子：
16.6
通讯作者：
Shi L
中科院分区：
文献类型：
--
作者：
Li X;Song N;Liu L;Liu X;Ding X;Song X;Yang S;Shan L;Zhou X;Su D;Wang Y;Zhang Q;Cao C;Ma S;Yu N;Yang F;Wang Y;Yao Z;Shang Y;Shi L
有缺陷的中心体复制与小头畸形和原始侏儒症以及各种纤毛病和癌症有关。然而，中心体生物发生是如何调节的仍然知之甚少。在此，我们报道 X-连锁去泛素酶 USP9X 与中心粒卫星蛋白 CEP131 物理相关，从而通过其去泛素酶活性稳定 CEP131。我们证明 USP9X 是中心体的一个组成部分，并且是中心体生物发生所必需的。 USP9X 的功能丧失会损害中心体复制，而 USP9X 的功能获得会促进中心体扩增和染色体不稳定。值得注意的是，USP9X在乳腺癌中过度表达，其表达水平与CEP131和更高组织学分级的乳腺癌相关。事实上，USP9X 通过调节 CEP131 丰度，促进乳腺癌发生。我们的实验确定 USP9X 是中心体生物发生的重要调节因子，并揭示了 USP9X/CEP131 在乳腺癌发生中的关键作用，支持将 USP9X/CEP131 作为乳腺癌干预的潜在靶点。 USP9X 是一种去泛素化酶，具有许多已知的底物和功能；它与癌症有关，但其机制仍不清楚。这里李等人。报告称 USP9X 稳定中心体蛋白 CEP131，导致中心体扩增和乳腺癌发展。
Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well as various ciliopathies and cancers. Yet, how the centrosome biogenesis is regulated remains poorly understood. Here we report that the X-linked deubiquitinase USP9X is physically associated with centriolar satellite protein CEP131, thereby stabilizing CEP131 through its deubiquitinase activity. We demonstrate that USP9X is an integral component of centrosome and is required for centrosome biogenesis. Loss-of-function of USP9X impairs centrosome duplication and gain-of-function of USP9X promotes centrosome amplification and chromosome instability. Significantly, USP9X is overexpressed in breast carcinomas, and its level of expression is correlated with that of CEP131 and higher histologic grades of breast cancer. Indeed, USP9X, through regulation of CEP131 abundance, promotes breast carcinogenesis. Our experiments identify USP9X as an important regulator of centrosome biogenesis and uncover a critical role for USP9X/CEP131 in breast carcinogenesis, supporting the pursuit of USP9X/CEP131 as potential targets for breast cancer intervention. USP9X is a deubiquitinating enzyme with many known substrates and functions; it has been linked to cancer but the mechanisms remain unclear. Here Li et al. report that USP9X stabilizes the centrosomal protein CEP131 leading to centrosome amplification and breast cancer development.