title: 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.affiliation: 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.
authors.forename: De
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Linchong
authors.initials: L
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.affiliation: 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.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhong
authors.affiliation: 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.
authors.forename: Dongya
authors.initials: D
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D015227:Lipid Peroxidation; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C455622:PPARGC1B protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase