Stress-Mediated Reprogramming of Prostate Cancer One-Carbon Cycle Drives Disease Progression.

One carbon (1C) metabolism has a key role in metabolic programming with both mitochondrial (m1C) and cytoplasmic (c1C) components. Here we show that Activating Transcription Factor 4 (ATF4) exclusively activates gene expression involved in m1C, but not c1C cycle in prostate cancer (PCa) cells. This includes activation of Methylenetetrahydrofolate dehydrogenase 2(MTHFD2) expression, the central player in the m1C cycle. Consistent with the key role of m1C cycle in PCa, MTHFD2 knockdown inhibited PCa cell growth, prostatosphere formation and growth of patient-derived xenograft (PDX) organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in a preclinical PCa mouse model. Consistently, MTHFD2 expression is significantly increased in human PCa and a gene expression signature based on the m1C cycle has significant prognostic value. Furthermore, MTHFD2 expression is coordinately regulated by ATF4 and the oncoprotein c-MYC, which has been implicated in PCa. These data suggest that the m1C cycle is essential for PCa progression and may serve as a novel biomarker and therapeutic target.