The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity
Abstract
Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET–SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Zishan Jiao
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Mi Zhang
Guangdong Provincial Key Laboratory of Carbon Dioxide Resource Utilization, School of Chemistry
Jingyuan Ning
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Han Yao
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaojun Yan
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Zhen Wu
Dexuan Wu
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Yajing Liu
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Meng Zhang
Lin Wang
Donglai Wang
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College