USP1 links platinum resistance to cancer cell dissemination by regulating Snail stability.
Sci Adv
; 5(5): eaav3235, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-31086816
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Platina
/
Apoptose
/
Complexos de Coordenação
/
Proteases Específicas de Ubiquitina
/
Fatores de Transcrição da Família Snail
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Sci Adv
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália