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 nontargeted metabolomic analysis, we identify the oncoprotein 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, while 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. Instead, pharmacological targeting of cellular SHMT 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 loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, overexpression of SET and SHMT2 are 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 critical mechanism for aberrant SET-driven tumorigenesis.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11711 | MetaboLights | 2025-04-22

REPOSITORIES: MetaboLights