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WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation

Woo-Jeong Jeong1,2, Jong-Chan Park1,2, Woo-Shin Kim1,2

  • 1Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.

Nature Communications
|January 19, 2019
PubMed

Insights

WD40-repeat protein 76 (WDR76) degrades RAS proteins, inhibiting liver cancer cell growth and invasion. WDR76 acts as a tumor suppressor by promoting RAS degradation, reducing liver carcinogenesis.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • RAS protein stability is crucial for its activity and is dysregulated in human cancers.
  • Mechanisms regulating RAS stability and their role in tumorigenesis are not fully understood.

Purpose of the Study:

  • To identify novel regulators of RAS stability.
  • To investigate the role of WD40-repeat protein 76 (WDR76) in RAS regulation and liver cancer.

Main Methods:

  • Proteomic analysis of hepatocellular carcinoma (HCC) tissues to identify HRAS binding proteins.
  • Investigating WDR76's function as an E3 linker protein.
  • Assessing the impact of WDR76-mediated RAS degradation on cancer cell behavior in vitro and in vivo.
  • Utilizing WDR76 knockout and inducible mouse models for liver carcinogenesis studies.

Main Results:

  • WDR76 was identified as an HRAS binding protein and functions as an E3 linker, mediating polyubiquitination-dependent RAS degradation.
  • WDR76-induced RAS destabilization inhibited proliferation, transformation, and invasion of liver cancer cells.
  • WDR76 deficiency increased susceptibility to chemically induced liver cancer, while WDR76 induction suppressed tumorigenesis in a mouse model.
  • An inverse correlation between WDR76 and RAS expression was observed in HCC tissues.

Conclusions:

  • WDR76 acts as a tumor suppressor by promoting RAS degradation.
  • WDR76-mediated RAS destabilization is a key mechanism for inhibiting liver cancer progression.
  • WDR76 represents a potential therapeutic target for liver cancer treatment.

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