title: The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells.
abstract: The induction of hypoxia-inducible factors (HIFs) is essential for the adaptation of tumor cells to a low-oxygen environment. We found that the expression of the apoptosis inhibitor ARC (apoptosis repressor with a CARD domain) was induced by hypoxia in a variety of cancer cell types, and its induction is primarily HIF1 dependent. Chromatin immunoprecipitation (ChIP) and reporter assays also indicate that the ARC gene is regulated by direct binding of HIF1 to a hypoxia response element (HRE) located at bp -190 upstream of the transcription start site. HIFs play an essential role in the pathogenesis of renal cell carcinoma (RCC) under normoxic conditions, through the loss of the Von Hippel-Lindau gene (VHL). Accordingly, our results show that ARC is not expressed in normal renal tissue but is highly expressed in 65% of RCC tumors, which also express high levels of carbonic anhydrase IX (CAIX), a HIF1-dependent protein. Compared to controls, ARC-deficient RCCs exhibited decreased colony formation and increased apoptosis in vitro. In addition, loss of ARC resulted in a dramatic reduction of RCC tumor growth in SCID mice in vivo. Thus, HIF-mediated increased expression of ARC in RCC can explain how loss of VHL can promote survival early in tumor formation.
authors.affiliation: Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Razorenova
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.forename: Renata
authors.initials: R
authors.lastname: Colavitti
authors.forename: Laura E
authors.initials: LE
authors.lastname: Edgington
authors.forename: Monica
authors.initials: M
authors.lastname: Nicolau
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
authors.forename: Edward M
authors.initials: EM
authors.lastname: Mills
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000386:AIDS-Related Complex / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein