Abstract
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.
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Acknowledgements
We thank M Bieri from University Hospital Zurich for preparing the script and establishing a novel formula for TMA staining intensity measurement, M Storz and S Dettwiler from the tissue biobank, A Fitsche, O Büchi and C Mittmann from the University Hospital Zurich for the excellent technical support, Professor I Frew from the University of Zurich and Dr T O’Connor from the Technical University of Munich for their critical input and reading the manuscript. This work was supported by the Swiss National Science Foundation Grants (3238BO-103145 and Sinergia) to HM; European Research Council (ERC) starting grant, a grant by the Stiftung für experimentelle Biomedizin (Peter-Hans Hofschneider foundation), the pre-clinical comprehensive center (PCCC), the SFB-TR36 and the Else Kröner-Fresenius Foundation to MH. AMN was supported by the NCCR-Kidney.ch.
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Nowicka, A., Häuselmann, I., Borsig, L. et al. A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization. Oncogene 35, 3125–3138 (2016). https://doi.org/10.1038/onc.2015.400
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DOI: https://doi.org/10.1038/onc.2015.400
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