HIF-1-Mediated Suppression of Acyl-CoA Dehydrogenases and Fatty Acid Oxidation Is Critical for Cancer Progression

•HIF-1 suppresses FAO in cancer cells by inhibiting MCAD and LCAD expression•HIF-1-mediated FAO suppression promotes cancer proliferation in part by reducing ROS•Suppression of LCAD, but not MCAD, blunted PTEN expression and enhanced tumor growth•Decreased LCAD expression in human HCC predicts patient mortality

SummaryHypoxia-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.

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