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 | |
dc.contributor.author | Senchenko, VN | |
dc.contributor.author | Kudryavtseva, AV | |
dc.contributor.author | Nickerson, ML | |
dc.contributor.author | Merino, M | |
dc.contributor.author | Hong, JA | |
dc.contributor.author | Schrump, DS | |
dc.contributor.author | Srinivasan, R | |
dc.contributor.author | Linehan, WM | |
dc.contributor.author | Tian, X | |
dc.contributor.author | 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 | ||
dc.identifier | onc2011179 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.uri | ||
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 | |
dc.subject | Basic Helix-Loop-Helix Transcription Factors | |
dc.subject | Carcinoma, Renal Cell | |
dc.subject | Cell Line, Tumor | |
dc.subject | DNA Methylation | |
dc.subject | Endogenous Retroviruses | |
dc.subject | Humans | |
dc.subject | Kidney Neoplasms | |
dc.subject | Promoter Regions, Genetic | |
dc.subject | Proviruses | |
dc.subject | Terminal Repeat Sequences | |
dc.subject | 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 | ||
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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