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

Nat Commun. 2019 Jan 17;10(1):295. doi: 10.1038/s41467-018-08230-6.


Stability regulation of RAS that can affect its activity, in addition to the oncogenic mutations, occurs in human cancer. However, the mechanisms for stability regulation of RAS involved in their activity and its roles in tumorigenesis are poorly explored. Here, we identify WD40-repeat protein 76 (WDR76) as one of the HRAS binding proteins using proteomic analyses of hepatocellular carcinomas (HCC) tissue. WDR76 plays a role as an E3 linker protein and mediates the polyubiquitination-dependent degradation of RAS. WDR76-mediated RAS destabilization results in the inhibition of proliferation, transformation, and invasion of liver cancer cells. WDR76-/- mice are more susceptible to diethylnitrosamine-induced liver carcinogenesis. Liver-specific WDR76 induction destabilizes Ras and markedly reduces tumorigenesis in HRasG12V mouse livers. The clinical relevance of RAS regulation by WDR76 is indicated by the inverse correlation of their expressions in HCC tissues. Our study demonstrates that WDR76 functions as a tumor suppressor via RAS degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / chemically induced
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / surgery
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA-Binding Proteins
  • Diethylnitrosamine / toxicity
  • Fibroblasts
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Liver / pathology
  • Liver / surgery
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / surgery
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Primary Cell Culture
  • Protein Binding
  • Proteolysis
  • Proteomics / methods
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • WDR76 protein, human
  • Wdr76 protein, mouse
  • Diethylnitrosamine
  • HRAS protein, human
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)