Regulation of renal epithelial tight junctions by the von Hippel-Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of E-cadherin.
Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation.
Harten
Sarah K
SK
Division of Medicine, Rayne Institute, University College London, WC1E 6JJ, London, United Kingdom.
Shukla
Deepa
D
Barod
Ravi
R
Hergovich
Alexander
A
Balda
Maria S
MS
Matter
Karl
K
Esteban
Miguel A
MA
Maxwell
Patrick H
PH
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D062445:Claudin-1; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D009154:Mutation / Q000235:genetics; D062793:Occludin; D010641:Phenotype; D000071250:Snail Family Transcription Factors; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D002087:Butyrates; C568108:CLDN1 protein, human; D015820:Cadherins; D062445:Claudin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human