Daam2 driven degradation of VHL promotes gliomagenesis
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
Affiliations
Wenyi Zhu
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States
Saritha Krishna
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
Cristina Garcia
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
Chia-Ching John Lin
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
Bartley D Mitchell
Department of Neurosurgery, Baylor College of Medicine, Houston, United States
Kenneth L Scott
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, United States
Carrie A Mohila
Department of Pathology, Texas Children’s Hospital, Houston, United States
Chad J Creighton
Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Seung-Hee Yoo
Department of Biochemistry and Molecular Biology, The University of Texas Heath Science Center at Houston, Houston, United States
Hyun Kyoung Lee
Department of Pediatrics, Division of Neurology, Baylor College of Medicine, Houston, United States; Neurological Research Institute, Texas Children’s Hospital, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United States
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States; Neurological Research Institute, Texas Children’s Hospital, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United States
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.
