USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells
文献类型：期刊论文
| 作者 | Lu, Qin2,3; Zhang, Fang-Lin2,3,4,5; Lu, Da-Yun6,7; Shao, Zhi-Ming1,2,3,4,5,8; Li, Da-Qiang1,2,3,4,5,8 |
| 刊名 | CANCER MEDICINE
 |
| 出版日期 | 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 |
| WOS记录号 | WOS:000493723000024 |
| 出版者 | WILEY |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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