title: VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail.
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.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Evans
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.forename: Olga
authors.initials: O
authors.lastname: Roche
authors.forename: T Nadine
authors.initials: TN
authors.lastname: Burry
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
authors.forename: Vinca W K
authors.initials: VW
authors.lastname: Chow
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Arthy
authors.initials: A
authors.lastname: Saravanan
authors.forename: Mindy A
authors.initials: MA
authors.lastname: Maynard
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Gervais
authors.forename: Roxana I
authors.initials: RI
authors.lastname: Sufan
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Roberts
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Wilson
authors.forename: Mark
authors.initials: M
authors.lastname: Betten
authors.forename: Cindy
authors.initials: C
authors.lastname: Vandewalle
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Michael A S
authors.initials: MA
authors.lastname: Jewett
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
mesh_terms: D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*
chemical_list: D015820:Cadherins; C108381:GEMIN2 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D012319:RNA Polymerase II; C497446:VHL protein, human