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Inactivation of the von Hippel–Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer

Oncogene volume 30, pages 4697–4706 (2011)Cite this article

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Abstract

A human endogenous retrovirus type E (HERV-E) was recently found to be selectively expressed in most renal cell carcinomas (RCCs). Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T cells that kill RCC cells in vitro and in vivo. Here, we show HERV-E expression is restricted to the clear cell subtype of RCC (ccRCC) characterized by an inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene with subsequent stabilization of hypoxia-inducible transcription factors (HIFs)-1α and -2α. HERV-E expression in ccRCC linearly correlated with HIF-2α levels and could be silenced in tumor cells by either transfection of normal VHL or small interfering RNA inhibition of HIF-2α. Using chromatin immunoprecipitation, we demonstrated that HIF-2α can serve as transcriptional factor for HERV-E by binding with HIF response element (HRE) localized in the proviral 5′ long terminal repeat (LTR). Remarkably, the LTR was found to be hypomethylated only in HERV-E-expressing ccRCC while other tumors and normal tissues possessed a hypermethylated LTR preventing proviral expression. Taken altogether, these findings provide the first evidence that inactivation of a tumor suppressor gene can result in aberrant proviral expression in a human tumor and give insights needed for translational research aimed at boosting human immunity against antigenic components of this HERV-E.

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Acknowledgements

This work was supported by the intramural research program of NIH, National Heart, Lung, and Blood Institute, Hematology Branch. We wish to acknowledge ACKC (Action to Cure Kidney Cancer) for their support of the ACKC fellow who conducted this research and the Dean R O’Neill Memorial Fellowship for generous contributions supporting this research. We also thank Bill and Giuliana Rancic for their contributions supporting kidney cancer research. We thank Robert Worrell for his assistance in providing tissue samples.

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Authors and Affiliations

  1. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    E Cherkasova, E Malinzak, S Rao, Y Takahashi, M I Lerman & R W Childs

  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

    V N Senchenko & A V Kudryavtseva

  3. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA

    M L Nickerson

  4. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    M Merino

  5. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    J A Hong & D S Schrump

  6. Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    R Srinivasan & W M Linehan

  7. Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    X Tian

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  1. E Cherkasova
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  2. E Malinzak
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  9. J A Hong
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Correspondence to R W Childs.

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Cherkasova, E., Malinzak, E., Rao, S. et al. Inactivation of the von Hippel–Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene 30, 4697–4706 (2011). https://doi.org/10.1038/onc.2011.179

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