Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer.
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.
Type
Journal articleSubject
5' Untranslated RegionsBasic Helix-Loop-Helix Transcription Factors
Carcinoma, Renal Cell
Cell Line, Tumor
DNA Methylation
Endogenous Retroviruses
Humans
Kidney Neoplasms
Promoter Regions, Genetic
Proviruses
Terminal Repeat Sequences
Von Hippel-Lindau Tumor Suppressor Protein
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https://hdl.handle.net/10161/10754Published Version (Please cite this version)
10.1038/onc.2011.179Publication Info
Cherkasova, E; Malinzak, E; Rao, S; Takahashi, Y; Senchenko, VN; Kudryavtseva, AV;
... Childs, RW (2011). Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression
of a human endogenous retrovirus in kidney cancer. Oncogene, 30(47). pp. 4697-4706. 10.1038/onc.2011.179. Retrieved from https://hdl.handle.net/10161/10754.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Elizabeth Malinzak
Associate Professor of Anesthesiology

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