HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity

Huafeng Zhang, Ping Gao, Ryo Fukuda, Ganesh Kumar, Balaji Krishnamachary, Karen I. Zeller, Chi V V. Dang, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

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 O2 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-1β is C-MYC dependent and that loss of PGC-1β expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.

Original languageEnglish (US)
Pages (from-to)407-420
Number of pages14
JournalCancer cell
Volume11
Issue number5
DOIs
StatePublished - May 8 2007

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity'. Together they form a unique fingerprint.

Cite this