USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells

doi:10.1002/cam4.2528

	USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells
	Lu, Qin 2,3; Zhang, Fang-Lin 2,3,4,5; Lu, Da-Yun 6,7; Shao, Zhi-Ming 1,2,3,4,5,8; Li, Da-Qiang 1,2,3,4,5,8
刊名	CANCER MEDICINE
	2019-11-01
卷号	8 期号:15 页码:6730-6740
关键词	BRCA1 breast cancer deubiquitinase PARP inhibitor USP9X
ISSN号	2045-7634
DOI	10.1002/cam4.2528
通讯作者	Shao, Zhi-Ming(zhimingshao@yahoo.com) ; Li, Da-Qiang(daqiangli1974@fudan.edu.cn)
英文摘要	BRCA1, a multifunctional protein with an important role in DNA double-strand break repair by homologous recombination (HR), is subjected to ubiquitin-dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin-specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small-molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild-type USP9X, but not its deubiquitinase activity-defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half-life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X-depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA-damaging agents.
WOS关键词	DEUBIQUITYLATING ENZYME ; TUMOR-SUPPRESSOR ; PROMOTES ; PROTEIN ; REPAIR ; TUMORIGENESIS ; DEGRADATION ; CONTRIBUTES ; SENSITIVITY ; INTERACTS
WOS研究方向	Oncology
语种	英语
出版者	WILEY
WOS记录号	WOS:000493723000024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282362]
专题	中国科学院上海药物研究所
通讯作者	Shao, Zhi-Ming; Li, Da-Qiang
作者单位	1.Fudan Univ, Shanghai Med Coll, Dept Breast Surg, Shanghai, Peoples R China 2.Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Shanghai 200032, Peoples R China 3.Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai 200032, Peoples R China 4.Fudan Univ, Shanghai Med Coll, Canc Inst, Shanghai, Peoples R China 5.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 8.Fudan Univ, Shanghai Med Coll, Key Lab Breast Canc Shanghai, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Lu, Qin,Zhang, Fang-Lin,Lu, Da-Yun,et al. USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells[J]. CANCER MEDICINE,2019,8(15):6730-6740.
APA	Lu, Qin,Zhang, Fang-Lin,Lu, Da-Yun,Shao, Zhi-Ming,&Li, Da-Qiang.(2019).USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells.CANCER MEDICINE,8(15),6730-6740.
MLA	Lu, Qin,et al."USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells".CANCER MEDICINE 8.15(2019):6730-6740.