Yi Yong, Wang Guoqiang, Zhang Wenhua, Yu Shuhan, Fei Junjie, An Tingting, Yi Jianqiao, Li Fengtian, Huang Ting, Yang Jian, Niu Mengmeng, Wang Yang, Xu Chuan, Xiao Zhi-Xiong Jim
Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Nat Commun. 2025 Jan 2;16(1):212. doi: 10.1038/s41467-024-55768-9.
Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers.
葡萄糖剥夺是肿瘤微环境的一个标志，它迫使肿瘤细胞寻找替代能源以维持生存和生长。在此，我们表明，葡萄糖剥夺会上调线粒体细胞色素c氧化酶II（MT-CO2）的表达，MT-CO2是呼吸链复合体IV的一个必需亚基，在促进谷氨酰胺分解代谢和维持肿瘤细胞存活方面发挥作用。从机制上讲，葡萄糖剥夺激活Ras信号以增强MT-CO2转录，并抑制RNA结合蛋白IGF2BP3以稳定MT-CO2 mRNA。MT-CO2升高会增加黄素腺嘌呤二核苷酸（FAD）水平，从而激活赖氨酸特异性去甲基化酶1（LSD1），进而表观遗传上调JUN转录，最终促进谷氨酰胺酶-1（GLS1）和谷氨酰胺分解代谢以维持肿瘤细胞存活。此外，MT-CO2对于致癌Ras诱导的谷氨酰胺分解代谢和肿瘤生长不可或缺，MT-CO2表达升高与肺癌患者的不良预后相关。总之，这些发现揭示了MT-CO2在适应代谢应激中的作用，并突出了MT-CO2作为Ras驱动癌症的一个潜在治疗靶点。
