Nuclear Receptor Nur77 Promotes Fatty Acid Oxidation By Regulating TPβ Enzyme Activity

Nur77 is a member of the steroid/thyroid/retinoid receptor superfamily and plays an important role in tumor metabolic regulation[1].In our previous study,we found that the deficiency of Nur77 could result in higher ROS level,leading cell death under glucose deprivation.Nur77 could be phosphorylated by the ROS-simulated ERK pathway and then translocated to the mitochondria.However,how Nur77 regulates ROS level in the mitochondria is still largely unknow.In this study,we illuminate a novel mechanism that Nur77 regulates the fatty acids oxidation by interacting with TPβ(trifunctional protein β)under glucose deprivation.TPβ acts as a thiolase in the last step of β oxidation.In the detection of the KACT(3-ketoacyl-CoA thiolase)activity and oxidative level of TPβ,to our surprise,glucose deprivation-induced ROS could oxidate TPβ and inhibit its KACT activity.However,Nur77 could suppress TPβ oxidation to protect the KACT activity.Knockdown of either Nur77 or TPβ not only affected cell survival in the suspended cells,but also inhibited circulating tumor cells survival and lung cancer cell metastasis assays in the mouse models.In conclusion,this study demonstrates the mechanism that Nur77 enhances the fatty acids oxidation by protecting TPβ KACT activity under glucose deprivation.This novel discovery not only provides a new thought for the clinical treatment of high metastatic tumors,but also provides a new target for the development of therapeutics in melanoma.