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

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 (W...

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Vydané v:	Nature communications Ročník 10; číslo 1; s. 295 - 11
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 17.01.2019 Nature Publishing Group Nature Portfolio
Predmet:	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 Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumorigenesis Tumors Ubiquitin-protein ligase Ubiquitination
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-08230-6