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VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail ^,

Andrew J. Evans,^1,2, Ryan C. Russell,^1, Olga Roche,^1, T. Nadine Burry,¹ Jason E. Fish,³ Vinca W. K. Chow,¹ William Y. Kim,⁴ Arthy Saravanan,² Mindy A. Maynard,¹ Michelle L. Gervais,¹ Roxana I. Sufan,¹ Andrew M. Roberts,¹ Leigh A. Wilson,¹ Mark Betten,⁵ Cindy Vandewalle,⁶ Geert Berx,⁶ Philip A. Marsden,^3,7 Meredith S. Irwin,^8,9 Bin T. Teh,⁵ Michael A. S. Jewett,¹⁰ and Michael Ohh^1*

Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada,¹ Department of Pathology, University Health Network, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada,² Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada,³ Department of Hematology Oncology, The Lineberger Comprehensive Cancer Center, 102 Mason Farm Road, CB7295, University of North Carolina, Chapel Hill, North Carolina 27599,⁴ Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, Michigan 49503,⁵ Department for Molecular Biomedical Research, Molecular and Cellular Oncology, VIB-Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium,⁶ Renal Division and Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, Ontario M5S 1A8, Canada,⁷ Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,⁸ Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada,⁹ and Departments of Urology and Surgical Oncology, University Health Network, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada,¹⁰

Received 18 May 2006/ Returned for modification 27 June 2006/ Accepted 27 September 2006

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 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 HIF in CC-RCC (VHL^–/–) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants 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.

Published ahead of print on 23 October 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

A.J.E., R.C.R., and O.R. contributed equally to this work.

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