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

dc.contributor.author

Cherkasova, E

dc.contributor.author

Malinzak, E

dc.contributor.author

Rao, S

dc.contributor.author

Takahashi, Y

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Senchenko, VN

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Kudryavtseva, AV

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Nickerson, ML

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Merino, M

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Hong, JA

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Schrump, DS

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Srinivasan, R

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Linehan, WM

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Tian, X

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Lerman, MI

dc.contributor.author

Childs, RW

dc.coverage.spatial

England

dc.date.accessioned

2015-10-20T13:44:13Z

dc.date.issued

2011-11-24

dc.description.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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/21602888

dc.identifier

onc2011179

dc.identifier.eissn

1476-5594

dc.identifier.uri

https://hdl.handle.net/10161/10754

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Oncogene

dc.relation.isversionof

10.1038/onc.2011.179

dc.subject

5' Untranslated Regions

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Basic Helix-Loop-Helix Transcription Factors

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Carcinoma, Renal Cell

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Cell Line, Tumor

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DNA Methylation

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Endogenous Retroviruses

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Humans

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Kidney Neoplasms

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Promoter Regions, Genetic

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Proviruses

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Terminal Repeat Sequences

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Von Hippel-Lindau Tumor Suppressor Protein

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Malinzak, E|0000-0002-0059-6567

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/21602888

pubs.begin-page

4697

pubs.end-page

4706

pubs.issue

47

pubs.organisational-group

Anesthesiology

pubs.organisational-group

Anesthesiology, General, Vascular, High Risk Transplant & Critical Care

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

30

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