VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail.
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.
Evans
Andrew J
AJ
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
RC
Roche
Olga
O
Burry
T Nadine
TN
Fish
Jason E
JE
Chow
Vinca W K
VW
Kim
William Y
WY
Saravanan
Arthy
A
Maynard
Mindy A
MA
Gervais
Michelle L
ML
Sufan
Roxana I
RI
Roberts
Andrew M
AM
Wilson
Leigh A
LA
Betten
Mark
M
Vandewalle
Cindy
C
Berx
Geert
G
Marsden
Philip A
PA
Irwin
Meredith S
MS
Teh
Bin T
BT
Jewett
Michael A S
MA
Ohh
Michael
M
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*
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