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

Woo-Jeong Jeong, Jong-Chan Park, Woo-Shin Kim, Eun Ji Ro, Soung Hoo Jeon, Sang-Kyu Lee, Young Nyun Park, Do Sik Min and Kang-Yell Choi ()
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Woo-Jeong Jeong: Yonsei University
Jong-Chan Park: Yonsei University
Woo-Shin Kim: Yonsei University
Eun Ji Ro: Yonsei University
Soung Hoo Jeon: Yonsei University
Sang-Kyu Lee: Yonsei University
Young Nyun Park: Yonsei University College of Medicine
Do Sik Min: Yonsei University
Kang-Yell Choi: Yonsei University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-08230-6

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