Daam2 driven degradation of VHL promotes gliomagenesis

• Main Authors: Wenyi Zhu, Saritha Krishna, Cristina Garcia, Chia-Ching John Lin, Bartley D Mitchell, Kenneth L Scott, Carrie A Mohila, Chad J Creighton, Seung-Hee Yoo, Hyun Kyoung Lee, Benjamin Deneen
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2017-10-01
• Series: eLife
• Subjects: Cancer Biology; Human; Mouse
• Online Access: https://elifesciences.org/articles/31926

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.