Daam2 driven degradation of VHL promotes gliomagenesis
Year: 2017
Type: article
Abstract: 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.
Source: eLife
DOI: 10.7554/elife.31926
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Cancer Research Institute, National Multiple Sclerosis Society, Cancer Prevention and Research Institute of Texas, Sontag Foundation, National Institutes of Health, University of Texas MD Anderson Cancer Center, Intellectual and Developmental Disabilities Research Center, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1267515642, G132965223, G1619438925, G1727840030, The nature of astrocyte heterogeneity in RTT, G3156146763, G3213366809, Baylor Intellectual and Developmental Disabilities Research Centers, Regulation and function of the circadian factor Period2, Decoding Cellular Heterogeneity of Malignant Glioma, Transcriptional Control of Gliogenesis in the CNS, G8108785121, Personalized Functionalization of Pediatric High Grade Glioma, Cancer Center Support Grant
OpenAlex ID: W2616496963