WSB1 promotes tumor metastasis by inducing pVHL degradation.

pVHL is ubiquitously expressed in normal tissues and functions as a tumor suppressor (Los et al. 1996; Gossage et al. 2015). Loss of pVHL via gene and germline mutations results in the von Hippel-Lindau (VHL) disease and is characterized by development of various tumors, including renal clear cell carcinomas (RCCs) and other highly vascularized tumors (Kaelin 2007; Bausch et al. 2013; Gossage et al. 2015). pVHL is the substrate recognition component of a cullin RING ubiquitin ligase complex that includes elongin B, elongin C, Rbx1, and Cul2 (Kaelin 2008; Deshaies and Joazeiro 2009). pVHL's main function as an E3 ligase is to target hypoxia-inducible factor-α (HIF-α) for degradation during normoxia (Gossage et al. 2015). Loss of pVHL function results in constitutive activation of HIF-1α and HIF-2α, which act as important heterodimeric transcription factors (composed of HIF-1α or HIF-2α and HIF-1β) for target genes such as VEGF, GULT1, CAIX, and HK2 (Semenza 2011; Keith et al. 2012; Montagner et al. 2012; Gossage et al. 2015). Constitutive activation of these transcription factors results in the induction of metabolic adaptation and promotes tumor growth, invasion, migration, metastasis, and angiogenesis through the up-regulation of their target genes (Majmundar et al. 2010; Semenza 2010, 2011; Keith et al. 2012). However, the regulation of pVHL at the post-transcriptional level remains underexplored. It has been reported that pVHL may be regulated through the ubiquitin–proteasome pathway (Jung et al. 2006; Chen et al. 2013; Pozzebon et al. 2013), although pVHL's E3 ligase has yet to be identified. Identification of how pVHL is regulated at the post-transcriptional level will further elucidate the mechanism of HIF biology in cancers, especially in cancers with wild-type pVHL. WSB1 (WD repeat and SOCS box-containing protein 1) has been classified as a substrate recognition subunit of the ECS (Elongin B/C–Cul2/5–SOCS) ubiquitin ligase complexes (Vasiliauskas et al. 1999). WSB1 harbors seven WD40 repeats and a SOCS box, respectively (Choi et al. 2008). WSB1 has been shown to be overexpressed in several cancers, such as pancreatic cancer, hepatocellular carcinoma, and salivary gland tumor (Rhodes and Chinnaiyan 2005; Archange et al. 2008; Silva et al. 2011; Tong et al. 2013). Additionally, WSB1 has been identified as a HIF-1 target gene (Tong et al. 2013). The cellular function of WSB1 is not well studied. WSB1 has been shown to mediate homeodomain-interacting protein kinase 2 (HIPK2) ubiquitination, resulting in its proteasome degradation (Choi et al. 2008). Following DNA damage, WSB1-mediated ubiquitination of HIPK2 is blocked, and HIPK2 is stabilized. HIPK2 in turn phosphorylates p53 at Ser46, which is important for activating proapoptotic gene expression (Puca et al. 2010). WSB1 overexpression has been shown to promote pancreatic cancer cell proliferation (Archange et al. 2008). However, it is unlikely that this effect is due to inactivation of the HIPK–p53 pathway, as the pancreatic cancer cell line used in this study contains mutant p53. This implies that WSB1 could promote cancer cell proliferation through other p53-independent mechanisms. Here, we identify WSB1 as a pVHL E3 ligase. In normoxic and hypoxic conditions, WSB1 interacts with pVHL and regulates pVHL's stability through proteasome degradation. These results reveal an important missing piece in the regulation of pVHL stability.