RT Journal Article
SR Electronic
T1 Daam2 Driven Degradation of VHL Promotes Gliomagenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 140277
DO 10.1101/140277
A1 Wenyi Zhu
A1 Saritha Krishna
A1 Cristina Garcia
A1 Chia-Ching John Lin
A1 Ken Scott
A1 Carrie A Mohila
A1 Chad J Creighton
A1 Seung-Hee Yoo
A1 Hyun Kyoung Lee
A1 Benjamin Deneen
YR 2017
UL http://biorxiv.org/content/early/2017/05/19/140277.abstract
AB Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.Statement of Significance We found that the glial developmental factor Daam2 promotes glioma tumorigenesis by suppressing VHL expression. Our studies show, for the first time, a regulatory mechanism that operates upstream of VHL in cancer and provides an explanation for how VHL expression is extinguished in tumors that do not have inactivating mutations.