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Sci Adv. 2019 May 8;5(5):eaav3235. doi: 10.1126/sciadv.aav3235. eCollection 2019 May.

USP1 links platinum resistance to cancer cell dissemination by regulating Snail stability.

Author information

1
Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, 33081 Aviano, Italy.
2
Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza," Santo Andrea Hospital, 00189 Rome, Italy.
3
University of Grenoble Alpes, CEA, INSERM, BIG-BGE, F-38000 Grenoble, France.
4
Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Wien, 1090 Vienna, Austria.
5
Genomica Funzionale, Fondazione G. Pascale, IRCCS, National Cancer Institute, 80100 Naples, Italy.
6
Anatomia Patologica, Fondazione G. Pascale, IRCCS, National Cancer Institute, 80100 Naples, Italy.

Abstract

Resistance to platinum-based chemotherapy is a common event in patients with cancer, generally associated with tumor dissemination and metastasis. Whether platinum treatment per se activates molecular pathways linked to tumor spreading is not known. Here, we report that the ubiquitin-specific protease 1 (USP1) mediates ovarian cancer cell resistance to platinum, by regulating the stability of Snail, which, in turn, promotes tumor dissemination. At the molecular level, we observed that upon platinum treatment, USP1 is phosphorylated by ATM and ATR and binds to Snail. Then, USP1 de-ubiquitinates and stabilizes Snail expression, conferring resistance to platinum, increased stem cell-like features, and metastatic ability. Consistently, knockout or pharmacological inhibition of USP1 increased platinum sensitivity and decreased metastatic dissemination in a Snail-dependent manner. Our findings identify Snail as a USP1 target and open the way to a novel strategy to overcome platinum resistance and more successfully treat patients with ovarian cancer.

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