Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival Under Metabolic Stress by Protecting Fatty Acid Oxidation

Xiao-Xue Li  ¹ , Zhi-Jing Wang  ¹ , Yu Zheng  ¹ , Yun-Feng Guan  ¹ , Peng-Bo Yang  ¹ , Xiang Chen  ² , Cong Peng  ² , Jian-Ping He  ¹ , Yuan-Li Ai  ¹ , Sheng-Fu Wu  ¹ , Kun-Yi Chien  ³ , Qiao Wu  ⁴ , Hang-Zi Chen  ⁵

• ¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, China.
• ² Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
• ³ Molecular Medicine Research Center, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
• ⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, China. Electronic address: qiaow@xmu.edu.cn.
• ⁵ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, China. Electronic address: chenhz@xmu.edu.cn.

Abstract

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

Keywords: FAO; ROS; TPβ; fatty acid oxidation; melanoma; metabolic stress; metastasis; mitochondrial trifunctional protein beta subunit; nuclear receptor Nur77/TR3; protein oxidation.