USP40 promotes hepatocellular carcinoma progression through a YAP/USP40 positive feedback loop

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Yes-associated protein (YAP) is a key driver of hepatocellular carcinoma (HCC) progression.
• The ubiquitin-proteasome system regulates YAP abundance, but the role of specific proteases is not fully understood.

Purpose of the Study:

• To investigate the role of ubiquitin-specific protease 40 (USP40) in regulating YAP stability and its impact on HCC.
• To elucidate the molecular mechanisms underlying the USP40-YAP interaction in HCC.

Main Methods:

• Co-immunoprecipitation to assess USP40-YAP interaction.
• Ubiquitination assays to determine USP40's deubiquitinating activity on YAP.
• In vitro cell assays (proliferation, colony formation, migration, spheroid formation) and in vivo HCC xenograft models.
• RNA sequencing to analyze gene expression changes.
• Analysis of clinical HCC patient data.

Main Results:

• USP40 directly interacts with YAP and removes K48-linked polyubiquitination at specific sites (K252, K315), stabilizing YAP.
• USP40 promotes HCC cell proliferation, migration, and tumor growth in a YAP-dependent manner.
• YAP transcriptionally upregulates USP40, forming a positive feedback loop.
• USP40 and YAP expression are positively correlated in HCC tissues, with high USP40 indicating poor prognosis.

Conclusions:

• A positive feedback loop between USP40 and YAP drives HCC progression.
• USP40 stabilizes YAP, enhancing its oncogenic functions in HCC.
• USP40 represents a potential therapeutic target for hepatocellular carcinoma treatment.