HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.
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.
Zhang
Huafeng
H
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Gao
Ping
P
Fukuda
Ryo
R
Kumar
Ganesh
G
Krishnamachary
Balaji
B
Zeller
Karen I
KI
Dang
Chi V
CV
Semenza
Gregg L
GL
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*
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