title: 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.
authors: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: E
authors: E
authors: Cherkasova
authors: E
authors: E
authors: Malinzak
authors: S
authors: S
authors: Rao
authors: Y
authors: Y
authors: Takahashi
authors: V N
authors: VN
authors: Senchenko
authors: A V
authors: AV
authors: Kudryavtseva
authors: M L
authors: ML
authors: Nickerson
authors: M
authors: M
authors: Merino
authors: J A
authors: JA
authors: Hong
authors: D S
authors: DS
authors: Schrump
authors: R
authors: R
authors: Srinivasan
authors: W M
authors: WM
authors: Linehan
authors: X
authors: X
authors: Tian
authors: M I
authors: MI
authors: Lerman
authors: R W
authors: RW
authors: Childs
references: N Engl J Med. 2000 Sep 14;343(11):750-8
references: 10984562
references: Nature. 1999 May 20;399(6733):271-5
references: 10353251
references: N Engl J Med. 2005 Dec 8;353(23):2477-90
references: 16339096
references: Mol Cancer. 2004 Apr 26;3:12
references: 15109395
references: Blood. 2002 Jun 1;99(11):4234-6
references: 12010834
references: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10589-94
references: 8855222
references: Semin Cancer Biol. 2010 Aug;20(4):246-53
references: 20685251
references: Cancer. 2009 May 15;115(10 Suppl):2262-72
references: 19402056
references: Cell Mol Life Sci. 2008 Nov;65(21):3366-82
references: 18818873
references: J Biol Chem. 2010 Apr 23;285(17):12916-24
references: 20185829
references: Gene. 2009 Dec 15;448(2):151-67
references: 19699787
references: Eur J Biochem. 1998 May 1;253(3):771-7
references: 9654078
references: Virology. 2009 Mar 1;385(1):261-6
references: 19070345
references: J Immunol. 2006 Aug 15;177(4):2056-60
references: 16887963
references: Oncogene. 2000 Nov 16;19(48):5435-43
references: 11114720
references: Cancer Res. 2002 May 15;62(10):2957-61
references: 12019178
references: Clin Cancer Res. 2008 Aug 1;14(15):4726-34
references: 18676741
references: Acta Oncol. 2009;48(6):909-14
references: 19322701
references: J Virol. 2005 Jan;79(2):876-83
references: 15613316
references: Blood. 2009 May 28;113(22):5568-74
references: 19336759
references: J Clin Invest. 2008 Mar;118(3):1099-109
references: 18292810
references: J Urol. 2006 May;175(5):1908-14
references: 16600797
references: Br J Cancer. 1999 Jul;80(9):1312-21
references: 10424731
references: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9
references: 8855223
references: AIDS Res Hum Retroviruses. 2008 May;24(5):717-23
references: 18462078
references: Nucleic Acids Res. 2010 Apr;38(7):2229-46
references: 20053729
references: Gene. 2009 Dec 15;448(2):105-14
references: 19577618
references: Cancer Res. 2008 Jul 15;68(14):5869-77
references: 18632641
references: J Clin Oncol. 2002 Apr 15;20(8):2017-24
references: 11956260