A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization.
Activation of hypoxia-inducible factor (HIF) is due to loss of von Hippel-Lindau protein (pVHL) function in most clear cell renal cell carcinomas (ccRCCs). Here we describe a novel pVHL-independent mechanism of HIF regulation and identify nuclear factor (NF)-κB essential modulator (NEMO) as a hitherto unknown oncogenic factor influencing human ccRCC progression. Over 60% of human ccRCCs (n=157) have negative or weak NEMO protein expression by immunohistochemistry. Moderate/strong NEMO protein expression is more frequent in VHL wild-type ccRCCs. We show that NEMO stabilizes HIFα via direct interaction and independently of NF-κB signaling in vitro. NEMO prolongs tumor cell survival via regulation of apoptosis and activation of epithelial-to-mesenchymal transition, facilitating tumor metastasis. Our findings suggest that NEMO-driven HIF activation is involved in progression of ccRCC. Therefore, NEMO may represent a clinically relevant link between NF-κB and the VHL/HIF pathways. Targeting NEMO with specific inhibitors in patients with metastatic ccRCC could be a novel treatment approach in patients with ccRCC expressing functional pVHL.
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
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AM
Nowicka
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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I
Häuselmann
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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0000-0003-2263-9545
L
Borsig
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
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S
Bolduan
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
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M
Schindler
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
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P
Schraml
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.|Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
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M
Heikenwalder
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
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H
Moch
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C491731:IKBKG protein, human; D016328:NF-kappa B; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051550:I-kappa B Kinase; C497446:VHL protein, human