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 Dang, Gregg L Semenza

Research output: Contribution to journalArticle

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

Fingerprint

Cell Respiration
Hypoxia-Inducible Factor 1
Organelle Biogenesis
Renal Cell Carcinoma
Respiration
Glycolysis
Proteasome Endopeptidase Complex
Genes
Neoplasms

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity. / Zhang, Huafeng; Gao, Ping; Fukuda, Ryo; Kumar, Ganesh; Krishnamachary, Balaji; Zeller, Karen I.; Dang, Chi V; Semenza, Gregg L.

In: Cancer Cell, Vol. 11, No. 5, 08.05.2007, p. 407-420.

Research output: Contribution to journalArticle

Zhang, Huafeng ; Gao, Ping ; Fukuda, Ryo ; Kumar, Ganesh ; Krishnamachary, Balaji ; Zeller, Karen I. ; Dang, Chi V ; Semenza, Gregg L. / HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity. In: Cancer Cell. 2007 ; Vol. 11, No. 5. pp. 407-420.
@article{bb42ef2f251a4f61b5ac30b72f1f5dca,
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 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.",
keywords = "CELLCYCLE",
author = "Huafeng Zhang and Ping Gao and Ryo Fukuda and Ganesh Kumar and Balaji Krishnamachary and Zeller, {Karen I.} and Chi V Dang and Semenza, {Gregg L}",
year = "2007",
month = "5",
day = "8",
doi = "10.1016/j.ccr.2007.04.001",
language = "English (US)",
volume = "11",
pages = "407--420",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity

AU - Zhang, Huafeng

AU - Gao, Ping

AU - Fukuda, Ryo

AU - Kumar, Ganesh

AU - Krishnamachary, Balaji

AU - Zeller, Karen I.

AU - Dang, Chi V

AU - Semenza, Gregg L

PY - 2007/5/8

Y1 - 2007/5/8

N2 - 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.

AB - 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.

KW - CELLCYCLE

UR - http://www.scopus.com/inward/record.url?scp=34247614521&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247614521&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2007.04.001

DO - 10.1016/j.ccr.2007.04.001

M3 - Article

C2 - 17482131

AN - SCOPUS:34247614521

VL - 11

SP - 407

EP - 420

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -