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

• Published in: Oncogene Vol. 30; no. 47; pp. 4697 - 4706
• Main Authors: Cherkasova, E, Malinzak, E, Rao, S, Takahashi, Y, Senchenko, V N, Kudryavtseva, A V, Nickerson, M L, Merino, M, Hong, J A, Schrump, D S, Srinivasan, R, Linehan, W M, Tian, X, Lerman, M I, Childs, R W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2011; Nature Publishing Group
• Subjects: 5' Untranslated Regions; 631/208/200; 631/67/581; 692/699/67/589/1588/1351; Antigens; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - physiology; Biological and medical sciences; Cancer; Carcinoma, Renal Cell - virology; Care and treatment; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromatin; Clear cells; Cytotoxicity; DNA Methylation; Endogenous Retroviruses - genetics; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Health aspects; Human endogenous retrovirus; Human Genetics; Humans; Hypoxia; Immunity; Immunogenicity; Immunoprecipitation; Immunotherapy; Internal Medicine; Kidney cancer; Kidney diseases; Kidney Neoplasms - etiology; Kidney Neoplasms - virology; Kidneys; Long terminal repeat; Lymphocytes T; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Neoplasia; Nephrology. Urinary tract diseases; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic; Proviruses - genetics; Regulatory sequences; Renal cell carcinoma; Retrovirus; Risk factors; siRNA; T cells; Terminal Repeat Sequences; Transcription factors; Transfection; Translation; Tumor cells; Tumor suppressor genes; Tumors; Tumors of the urinary system; VHL protein; Viruses; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - physiology; United States; DNA methylation; renal cell carcinoma; VHL; HIF; endogenous retrovirus; Carcinoma; Endogenous retrovirus; Cardiovascular disease; Inactivation; Carcinogenesis; Vascular disease; Grawitz tumor; Tumor suppressor gene; Kidney disease; Human; Nervous system diseases; Urinary system disease; Phacomatosis; Malignant tumor; Genetic disease; Von Hippel-Lindau disease; Eye disease; DNA; Central nervous system disease; Kidney cancer; Methylation; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.179

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.