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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Platinum-based chemotherapy is a cornerstone in cancer treatment but faces challenges due to acquired resistance.
• Tumor dissemination and metastasis are frequently associated with chemotherapy resistance, yet the underlying molecular mechanisms remain incompletely understood.
• The role of platinum treatment in activating pathways that promote tumor spreading is an open question.

Purpose of the Study:

• To investigate the role of ubiquitin-specific protease 1 (USP1) in mediating ovarian cancer cell resistance to platinum-based chemotherapy.
• To elucidate the molecular mechanisms by which USP1 influences tumor dissemination and metastatic potential.
• To identify USP1 as a potential therapeutic target for overcoming platinum resistance.

Main Methods:

• Utilized ovarian cancer cell models to assess platinum sensitivity.
• Investigated the interaction and regulation between USP1 and Snail following platinum treatment.
• Employed gene knockout and pharmacological inhibition strategies to target USP1.
• Assessed changes in stem cell-like features and metastatic ability.

Main Results:

• Platinum treatment induced phosphorylation of USP1 by ATM and ATR, leading to USP1 binding to Snail.
• USP1 de-ubiquitinates and stabilizes Snail, conferring platinum resistance, enhanced stem cell-like properties, and increased metastatic potential.
• USP1 knockout or inhibition restored platinum sensitivity and reduced metastatic dissemination in a Snail-dependent manner.

Conclusions:

• Identified Snail as a direct target of USP1 in the context of platinum chemotherapy.
• USP1 plays a critical role in mediating platinum resistance and promoting metastasis in ovarian cancer.
• Targeting USP1 presents a novel therapeutic strategy to overcome platinum resistance and improve treatment outcomes for ovarian cancer patients.