VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail

AJ Evans, RC Russell, O Roche, TN Burry… - … and cellular biology, 2007 - Taylor & Francis
AJ Evans, RC Russell, O Roche, TN Burry, JE Fish, VWK Chow, WY Kim, A Saravanan…
Molecular and cellular biology, 2007Taylor & Francis
The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition
component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic α subunit of
hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging
evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is
crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular
events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that …
The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic α subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL−/−) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFα in CC-RCC (VHL−/−) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFα degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established “gatekeeper” of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.
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