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Mol. Cell. Biol. doi:10.1128/MCB.00892-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

VHL Promotes E2 Box-dependent E-cadherin Transcription by HIF-mediated Regulation of SIP1 and Snail

Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Pathology, University Health Network, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Hematology Oncology, The Lineberger Comprehensive Cancer Center, 102 Mason Farm Road, CB7295, University of North Carolina, Chapel Hill, North Carolina 27599, U.S.A.; Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, U.S.A.; Department for Molecular Biomedical Research (DMBR), Molecular and Cellular Oncology, VIB-Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium; Renal Division and Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Departments of Urology and Surgical Oncology, University Health Network, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada

^* To whom correspondence should be addressed. Email: michael.ohh{at}utoronto.ca.

	Abstract

The product of von Hippel-Lindau (VHL) gene acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic 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. Re-introduction 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. RNAi-mediated knockdown of HIF in CC-RCC (VHL-/-) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutant incapable of promoting HIF 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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