The role of VHL in the regulation of E-cadherin: a new connection in an old pathway.

The von Hippel-Lindau (VHL) protein is a critical regulator of the ubiquitous oxygen-sensing pathway. VHL is a component of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor (HIFalpha) for ubiquitin-mediated destruction under normal oxygen tension. As a consequence of HIFalpha stabilization upon the functional loss of VHL, the cell constitutively upregulates the hypoxic program resulting in the inappropriate expression of genes responsible for global changes in angiogenesis, energy metabolism, and proliferation. The emerging evidence suggests that the inactivation of VHL-HIF pathway is critical for the development of clear-cell renal cell carcinoma (CC-RCC). Until recently, the downstream effector(s) of HIF responsible for the oncogenic transformation of renal epithelial cells remained largely unknown. This review highlights recent discoveries uncovering the transcriptional regulation of E-cadherin, a homophilic cell adhesion molecule with anti-invasive properties in numerous epithelial-derived cancers, via the VHL-HIF pathway.