ATR-dependent ubiquitin-specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Research

Background:

• Oxaliplatin (OXA) resistance presents a significant clinical challenge in hepatocellular carcinoma (HCC).
• Ferroptosis, an iron-dependent cell death pathway, is a potential strategy to restore chemosensitivity.
• Understanding mechanisms of drug resistance is crucial for improving HCC treatment outcomes.

Purpose of the Study:

• To investigate the role of USP20 in OXA resistance and ferroptosis in HCC.
• To elucidate the molecular mechanisms by which USP20 influences OXA resistance and ferroptosis.
• To explore USP20 as a potential therapeutic target for overcoming OXA resistance in HCC.

Main Methods:

• Analysis of USP20 expression in HCC tissues and cells.
• In vitro and in vivo experiments involving pharmacological inhibition and knockdown of USP20.
• Coimmunoprecipitation assays to determine protein interactions.
• Western blotting to assess protein ubiquitination and phosphorylation.
• Cell viability and ferroptosis assays.

Main Results:

• USP20 was overexpressed in OXA-resistant HCC cells and associated with poor prognosis.
• USP20 knockdown or inhibition restored OXA sensitivity and induced ferroptosis in HCC cells.
• USP20 directly interacted with SLC7A11, stabilizing it by removing K48-linked polyubiquitination.
• DNA damage-induced ATR activation phosphorylated USP20, enhancing its stability and conferring resistance.
• Targeting USP20 effectively mitigated drug resistance and promoted ferroptosis in HCC models.

Conclusions:

• USP20 plays a critical role in mediating OXA resistance and suppressing ferroptosis in HCC.
• USP20 stabilizes SLC7A11, contributing to chemoresistance.
• USP20 phosphorylation by ATR is a key mechanism for its stability and function in resistance.
• Targeting USP20 represents a promising therapeutic strategy to overcome OXA resistance and enhance ferroptosis in HCC patients.