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

• Published in: Nature communications Vol. 10; no. 1; pp. 295 - 11
• Main Authors: Jeong, Woo-Jeong, Park, Jong-Chan, Kim, Woo-Shin, Ro, Eun Ji, Jeon, Soung Hoo, Lee, Sang-Kyu, Park, Young Nyun, Min, Do Sik, Choi, Kang-Yell
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 49/88; 631/337/458/582; 631/45/612/1243; 631/45/612/1248; 631/67/1244; 631/67/395; 64/110; 64/60; 82/29; 82/51; 82/80; 96/1; 96/109; 96/95; Animals; Cancer; Carcinogenesis; Carcinogenesis - chemically induced; Carcinogenesis - pathology; Carcinogens; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - surgery; Cell Line, Tumor; Cell proliferation; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Degradation; Destabilization; Diethylnitrosamine; Diethylnitrosamine - toxicity; Fibroblasts; Gene Knockout Techniques; Genetic transformation; HEK293 Cells; Hepatocellular carcinoma; Hepatocytes; Humanities and Social Sciences; Humans; Liver; Liver - pathology; Liver - surgery; Liver cancer; Liver Neoplasms - pathology; Liver Neoplasms - surgery; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Mutation; Primary Cell Culture; Protein Binding; Proteins; Proteolysis; Proteomics - methods; Proto-Oncogene Proteins p21(ras) - metabolism; Ras protein; Science; Science (multidisciplinary); Stability; Tissues; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• 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 HRas G12V 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. Overexpression of RAS proteins is frequently observed in patients with hepatocellular carcinoma. Here, the authors identify an HRAS binding protein, the E3 ubiquitin ligase WDR76, which promotes HRAS degradation, thus functioning as a tumour suppressor in liver cancer