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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 6 Pg. 1930-1942 (Sep 25 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25242319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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