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

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 expressio...

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Bibliographic Details
Published in:Oncogene Vol. 30; no. 47; pp. 4697 - 4706
Main Authors: Cherkasova, E, Malinzak, E, Rao, S, Takahashi, Y, Senchenko, V N, Kudryavtseva, A V, Nickerson, M L, Merino, M, Hong, J A, Schrump, D S, Srinivasan, R, Linehan, W M, Tian, X, Lerman, M I, Childs, R W
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 24-11-2011
Nature Publishing Group
Subjects:
VHL
HIF
DNA
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Summary: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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ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2011.179