Daam2 driven degradation of VHL promotes gliomagenesis

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.

Dishevelled Associated Activator Of Morphogenesis (DAAM) Facilitates Invasion of Hepatocellular Carcinoma by Upregulating Hypoxia-Inducible Factor 1α (HIF-1α) Expression

“…The effect of DAAM1 knockdown was not notable on VHL and HIF-1α expression, whereas DAAM2 knockdown substantially increased VHL expression and consequently decreased HIF-1α expression ( Figure 3D ). This was inconsistent with previous results in glioma, which showed DAAM2-driven degradation of VHL [ 10 ]. To confirm the result, we overexpressed DAAM2 in HuH7 and HepG2, and verified the effects of DAAM2 overexpression on VHL and HIF-1α after treatment with 10 μM MG132 for 6 hr.…”

“…The knockdown of both DAAM1 and DAAM2 had blunting effects on proliferation, while the knockdown of DAAM2, instead of DAAM1, substantially decreased the invasion of HuH7 ( Figure 3B, 3C ). A previous study suggested that DAAM2 could reduce VHL expression by promoting its ubiquitination [ 10 ]. Moreover, HIF-1α is a well-accepted downstream protein regulated by VHL, and it is widely involved in the progression of numerous tumors [ 20 ].…”

“…For example, DAAM1 has been demonstrated to promote tumor progression in several cancers types, including breast and ovarian cancer [ 8 , 9 ]. Although several studies have suggested a tumor-promoting role for DAAM2 in some special tumors, such as glioma and renal cancer [ 10 , 11 ], less research has been done focusing on the oncogenic role of DAAM2 than on that of DAAM1. Moreover, expression and function of DAAM1 and DAAM2 in HCC are still obscure.…”

“…In normoxia, HIF-1α is hydroxylated by Prolyl hydroxylase domain proteins (PHDs) at prolines 402 and 564, then recognized by VHL and degraded in the E3 ubiquitin pathway [ 12 – 14 ]. Recent studies have shown that DAAM2 promotes degradation of VHL and facilitated gliomagenesis [ 10 ]. However, whether DAAM2 regulates VHL degradation and its downstream protein, HIF-1α, is unknown.…”

Whole exome sequencing identifies a rare variant in DAAM2 as a potential candidate in idiopathic pulmonary ossification

“…However, several genes, including ubiquitin-specific peptidase 17-like family member 8 (USP17L8), gammaglutamyltransferase light chain 2 (GGTLC2), mucin 3A (MUC3A), CTAGE family, member 6 (CTAGE6), SCOspondin (SSPO), proline-rich protein BstNI subfamily 3 (PRB3), SLAIN motif family, member 1 (SLAIN1) and axonemal central pair apparatus protein (HYDIN), have not been extensively studied, and both their functions and the significance of their variants should be further evaluated. DAAM2 may play an important role in the occurrence and development of lung, kidney, colorectal and glioma tumours (36)(37)(38)(39). DAAM2 was found to be elevated in the acute phase of Guillain-Barre syndrome through the Wnt signalling pathway (40).…”