Tumor hypoxia is associated with cancer progression, but the hypoxia signaling mechanism remains largely unclear.Here, we show that Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is required for hypoxic induction of glycolysis and suppression of mitochondrial respiration that reduces oxygen consumption and inhibits the ROS production, and promotes cancer cells survival in hypoxia.We fotmd that NAC1 mediates metabolic switch in hypoxia through activating transcription of pyruvate dehydrogenase kinase 3 (PDK3), thereby inhibiting pyruvate dehydrogenase (PDH) and attenuating pyruvate into mitochondrial oxidation.Forced expression of PDK3 in hypoxia NAC 1 absent cells rescues these cells from hypoxia-induced apoptosis.Furthermore, we show that over-expression of NAC1 correlates with PDH inactivation in ovarian cancer tissues and that NAC1 short-hairpin RNA (shRNA)-expression xenograft tumors are decreased in size, increased in apoptosis and metabolically changed.Our findings not only reveal a previously unrecognized function of NAC1 and its impact on tumor development, but also identify a novel metabolic regulator that may be exploited as a potential target for cancer prevention.
NAC1 metabolic switch PDK3 hypoxia
Zhang Y Ming ZJ Kai Lee Yap Wang JR Ie-Ming Shih Yang JM Cheng Y Zhang L Shan Y Ren YJ Ren XC Chen B Yang WQ Zhou L
Department of Pharmacology, College of Pharmaceutical Sciences, Cyrus Tang Hematology Center, Affili Department of Pathology, John Hopkins University School of Medicine, Baltimore, Maryland Department of Pharmacology, College of Pharmaceutical Sciences, Cyrus Tang Hematology Center, Affili Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College Institute of Botany, Jiangsu Province and Chinese Academy of Sciences