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
Affiliations
De Huang
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
Tingting Li
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
Xinghua Li
State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Long Zhang
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
Linchong Sun
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
Xiaoping He
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
Xiuying Zhong
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
Dongya Jia
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
Libing Song
State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Gregg L. Semenza
Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ping Gao
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
Huafeng Zhang
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
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.
