Daam2 driven degradation of VHL promotes gliomagenesis.

Wenyi Zhu,Carrie A Mohila,Cristina Garcia,Chia-Ching John Lin,Seung-Hee Yoo,Saritha Krishna,Chad J Creighton,Kenneth L Scott,Bartley D Mitchell,Hyun Kyoung Lee,Benjamin Deneen

doi:10.7554/elife.31926

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.

Highlights

Tumor suppressor and oncogenic pathways function in part by subverting existing cellular programs to promote cancer ‘hallmark’ properties that engender malignant growth (Hanahan and Weinberg, 2011)
To validate DAAM2 expression in human low-grade glioma (LGG) and glioblastoma multiforme (GBM), we used in situ hybridization (ISH) across a cohort of 35 LGG and 40 GBM primary human samples, finding that DAAM2 demonstrates heterogeneous expression within each glioma sub-type (Figure 1B–C; Figure 1—figure supplement 1)
Using factors critical for central nervous system (CNS) development as an entry point to identify new mechanisms that contribute to tumorigenesis, we found that the glial development factor, Daam2 promotes glioma tumorigenesis across human glioma cell lines and multiple mouse models of glioma

Summary

Introduction

Tumor suppressor and oncogenic pathways function in part by subverting existing cellular programs to promote cancer ‘hallmark’ properties that engender malignant growth (Hanahan and Weinberg, 2011). Genetic mutation is not the sole source of this dysregulation, as changes in gene expression via promoter methylation or protein turnover can phenotypically resemble driver mutations and contribute to tumorigenesis (Esteller et al, 1999; Hegi et al, 2004; Pineda et al, 2015; Reinstein and Ciechanover, 2006; Semenza, 2003; Shen et al, 2005; Zochbauer-Muller et al, 2001).

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Conclusion