USP9X regulates centrosome duplication and promotes breast carcinogenesis

Xin Li,Xiang Ding,Shangda Yang,Fuquan Yang,Xin Song,Cheng Cao,Zhi Yao,Xinhua Liu,Xing Zhou,Yue Wang,Dongxue Su,Shuai Ma,Yongfeng Shang,Shuo Lin ,Yan Wang,Ling Liu,Na Yu,Qi Zhang,Nan Song,Lei Shi

doi:10.1038/ncomms14866

Abstract

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.

Highlights

Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well as various ciliopathies and cancers
Proteomics analysis and molecular study suggest that CEP131 is a ubiquitinated protein[14,15], and, significantly, CEP131 has been reported to play an important role in the maintenance of the genome stability at the time of cell cycle progression[13], suggesting that CEP131 is required for proper centrosome duplication and hinting a potential role for this protein in cancer development and progression
The results revealed that USP9X is associated with multiple proteins including itchy E3 ubiquitin protein ligase (ITCH), an ubiquitin ligase known to be associated with USP9X

Summary

Introduction

Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well as various ciliopathies and cancers. 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. The molecular mechanism by which centrosome duplication is regulated and how centrosome amplification is introduced and contributes to cancer development/progression are still poorly understood. Proteomics analysis and molecular study suggest that CEP131 is a ubiquitinated protein[14,15], and, significantly, CEP131 has been reported to play an important role in the maintenance of the genome stability at the time of cell cycle progression[13], suggesting that CEP131 is required for proper centrosome duplication and hinting a potential role for this protein in cancer development and progression

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Results

Conclusion