机构：[1]State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao TongUniversity, Shanghai 200127, China[2]School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200240,China[3]Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China[4]State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University,Shanghai 200032, China[5]Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200050, China
MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
基金：
National Natural Science Foundation of China
(81472537 and 81672714 to G.Z.; 81502597 to Y.J.; 81472426 to W.D.), the Grants from
the State Key Laboratory of Oncogenes and Related Genes (No. 91-15-12 to G.Z.), the
grants from Shanghai Jiao Tong University School of Medicine (DLY201505 to W.D.;
YG2016MS51 to X.Y.), Shanghai Municipal Education Commission-Gaofeng Clinical
Medicine Grant Support (20161313 to G.Z.), the Shanghai Institutions of Higher
Learning (Eastern Scholar to G.Z.), Shanghai Rising-Star Program (16QA1403600 to G.
Z.), Shanghai Municipal Commission of Health and Family Planning (2013ZYJB0202
and 15GWZK0701 to W.D.; 20174Y0189 to Y.J.), the grant from Shanghai Key
Laboratory of Gynecologic Oncology (FKZL-2017-01 to Y.J.), and the grant from Science
and Technology Commission of Shanghai Municipality (16140904401 to X.Y.).
第一作者机构：[1]State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao TongUniversity, Shanghai 200127, China[2]School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200240,China
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao TongUniversity, Shanghai 200127, China[3]Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
推荐引用方式(GB/T 7714)：
Shengzhe Zhang,Meiying Zhang,Ying Jing,et al.Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors[J].NATURE COMMUNICATIONS.2018,9:doi:10.1038/s41467-017-02693-9.
APA：
Shengzhe Zhang,Meiying Zhang,Ying Jing,Xia Yin,Pengfei Ma...&Guanglei Zhuang.(2018).Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors.NATURE COMMUNICATIONS,9,
MLA：
Shengzhe Zhang,et al."Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors".NATURE COMMUNICATIONS 9.(2018)
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