title: HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.
abstract: Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.
authors.affiliation: Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Ryo
authors.initials: R
authors.lastname: Fukuda
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kumar
authors.forename: Balaji
authors.initials: B
authors.lastname: Krishnamachary
authors.forename: Karen I
authors.initials: KI
authors.lastname: Zeller
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D014158:Transcription, Genetic / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C455622:PPARGC1B protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D010100:Oxygen