Inactivation of the von Hippel–Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer
In: Oncogene, Jg. 30 (2011-05-23), S. 4697-4706
Online
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Zugriff:
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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Inactivation of the von Hippel–Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer
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Autor/in / Beteiligte Person: | Lerman, Michael I. ; Cherkasova, Elena ; Tian, Xin ; Srinivasan, Ramaprasad ; Hong, Julie ; Schrump, David S. ; Linehan, W. M. ; Senchenko, V. N. ; Elizabeth B Malinzak ; Rao, Sheila ; Nickerson, Michael L. ; Merino, Maria J. ; Childs, Richard W. ; Kudryavtseva, Anna V. ; Takahashi, Yoshiyuki |
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Zeitschrift: | Oncogene, Jg. 30 (2011-05-23), S. 4697-4706 |
Veröffentlichung: | Springer Science and Business Media LLC, 2011 |
Medientyp: | unknown |
ISSN: | 1476-5594 (print) ; 0950-9232 (print) |
DOI: | 10.1038/onc.2011.179 |
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