HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

De Huang; Tingting Li; Xinghua Li; Long Zhang; Linchong Sun; Xiaoping He; Xiuying Zhong; Dongya Jia; Libing Song; Gregg L Semenza; Ping Gao; Huafeng Zhang

doi:10.1016/j.celrep.2014.08.028

HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

Cell Rep. 2014 Sep 25;8(6):1930-1942. doi: 10.1016/j.celrep.2014.08.028. Epub 2014 Sep 18.

Authors

Affiliations

¹ Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China.
² State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
³ Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Institute for Cancer Research and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei 230027, China. Electronic address: hzhang22@ustc.edu.cn.

PMID: 25242319
DOI: 10.1016/j.celrep.2014.08.028

Abstract

Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1α also inhibits fatty acid β-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1β-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth in vivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyl-CoA Dehydrogenase / antagonists & inhibitors
Acyl-CoA Dehydrogenase / genetics
Acyl-CoA Dehydrogenase / metabolism*
Acyl-CoA Dehydrogenase, Long-Chain / antagonists & inhibitors
Acyl-CoA Dehydrogenase, Long-Chain / genetics
Acyl-CoA Dehydrogenase, Long-Chain / metabolism*
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation
Fatty Acids / metabolism*
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Kaplan-Meier Estimate
Lipid Peroxidation
Liver Neoplasms / metabolism
Liver Neoplasms / mortality
Liver Neoplasms / pathology*
Mitochondria / metabolism
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
RNA, Small Interfering / metabolism
RNA-Binding Proteins
Reactive Oxygen Species / metabolism

Substances

Carrier Proteins
Fatty Acids
Hypoxia-Inducible Factor 1, alpha Subunit
PPARGC1B protein, human
RNA, Small Interfering
RNA-Binding Proteins
Reactive Oxygen Species
Acyl-CoA Dehydrogenase
Acyl-CoA Dehydrogenase, Long-Chain
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase