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Molecular and Cellular Biology, January 2007, p. 157-169, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00892-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail{triangledown} ,{dagger}

Andrew J. Evans,1,2,{ddagger} Ryan C. Russell,1,{ddagger} Olga Roche,1,{ddagger} 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 Ohh1*

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

* Corresponding author. Mailing address: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Phone: (416) 946-7922. Fax: (416) 978-5959. E-mail: michael.ohh{at}utoronto.ca.

{triangledown} Published ahead of print on 23 October 2006.

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

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

Molecular and Cellular Biology, January 2007, p. 157-169, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00892-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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