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PMID: 17060462 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 27 ·No. 1 ·2007-01-00 ·Pages 157-69

Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, Sufan RI, Roberts AM, Wilson LA, Betten M, Vandewalle C, Berx G, Marsden PA, Irwin MS, Teh BT, Jewett MA, Ohh M

Abstract

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

MeSH Terms
Cadherins/biosynthesis,genetics,metabolism Cell Line, Tumor Epithelial Cells/metabolism Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Kidney/metabolism Nerve Tissue Proteins/physiology Promoter Regions, Genetic RNA Interference RNA Polymerase II/metabolism RNA, Small Interfering/metabolism RNA-Binding Proteins/physiology Snail Family Transcription Factors Subcellular Fractions/metabolism Transcription Factors/physiology Von Hippel-Lindau Tumor Suppressor Protein/physiology
Chemicals
Cadherins GEMIN2 protein, human HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Nerve Tissue Proteins RNA, Small Interfering RNA-Binding Proteins Snail Family Transcription Factors Transcription Factors Von Hippel-Lindau Tumor Suppressor Protein RNA Polymerase II VHL protein, human
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Evans Andrew J
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Russell Ryan C
Roche Olga
Burry T Nadine
Fish Jason E
Chow Vinca W K
Kim William Y
Saravanan Arthy
Maynard Mindy A
Gervais Michelle L
Sufan Roxana I
Roberts Andrew M
Wilson Leigh A
Betten Mark
Vandewalle Cindy
Berx Geert
Marsden Philip A
Irwin Meredith S
Teh Bin T
Jewett Michael A S
Ohh Michael
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00892-06
Published
2007-01-00
Epub
2006-00-23
Pages
157-69
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1800649
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.00892-06 PMC Full Text View journal details
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