In order to survive under conditions of low
oxygen,
cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of
reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a
nuclear protein of the BTB/POZ gene family, has pivotal roles in
cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects
cancer cells from apoptosis in
hypoxia. We show that NAC1 mediates suppression of mitochondrial function in
hypoxia through inducing expression of
pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating
pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from
hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of
elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during
cancer progression, and chemo-resistance in
cancer therapy.