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Vol. 20, Issue 3, 1089-1101, February 1, 2009
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*Division of Medicine, Rayne Institute, University College London, WC1E 6JJ, London, United Kingdom; Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland; Institute of Ophthalmology, University College London, EC1V 9EL London, United Kingdom; and South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China
Submitted June 6, 2008;
Revised December 2, 2008;
Accepted December 3, 2008
Monitoring Editor: Benjamin Margolis
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.
|| These authors contributed equally to this work.
Address correspondence to: Miguel A. Esteban (esteban{at}gibh.org)
Abbreviations used: AJ, adherens junction; CAIX, carbonic anhydrase IX; CCRCC, clear cell renal cell carcinomas; ECA, E-cadherin; EMT, epithelial-to-mesenchymal transition; GLUT1, glucose transporter 1; HDAC, histone deacetylase; HIF, hypoxia-inducible factor; N, normal tissue; PHD, prolyl hydroxylase domain; T, tumor tissue; TJ, tight junction; VHL, von Hippel-Lindau; ZO, zona occludens.
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