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

Abstract

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 the c1C cycle in prostate cancer 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 prostate cancer, MTHFD2 knockdown inhibited prostate cancer cell growth, prostatosphere formation, and growth of patient-derived xenograft organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in preclinical prostate cancer mouse models. Consistently, MTHFD2 expression is significantly increased in human prostate cancer, 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 prostate cancer. These data suggest that the m1C cycle is essential for prostate cancer progression and may serve as a novel biomarker and therapeutic target. Significance: These findings demonstrate that the mitochondrial, but not cytoplasmic, one-carbon cycle has a key role in prostate cancer cell growth and survival and may serve as a biomarker and/or therapeutic target.

Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)

“…50 Recently, a stress-mediated increase in MTHFD2, a key enzyme in the mitochondrial onecarbon cycle, was shown to be essential for prostate cancer progression. 56 One of the most dramatic changes in TRACK transcripts is a > 30-fold increase in Aldh1l2 (Figure 2A). This mitochondrial gene converts 10-formyl-tertrahydrofolate (THF) to THF/CO 2 + NADPH.…”

“…Importantly, the mitochondrial folate one‐carbon pathway functions as a source of one‐carbon units for high‐demand purine and thymidine nucleotide synthesis and epigenetic methylation reactions in cancers 50 . Recently, a stress‐mediated increase in MTHFD2, a key enzyme in the mitochondrial one‐carbon cycle, was shown to be essential for prostate cancer progression 56 . One of the most dramatic changes in TRACK transcripts is a > 30‐fold increase in Aldh1l2 (Figure 2A).…”

PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

“…To define the mechanism underlying the regulation of mitochondrial function by PPFIA4, we firstly analyzed the interactome of PPFIA4. Because MTHFD2 is the key enzyme for one-carbon metabolism in PCa progression [ 34 ], we selected MTHFD2 as the potential interactor with PPFIA4 in mitochondria (Fig. 5 A).…”

Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

“…Finally, the central component of the mitochondrial one-carbon metabolism MTHFD2 is upregulated in prostate cancer from at least two transcription factors ATF4 and c-Myc, which have already been implicated in this disease and its silencing inhibits prostate cancer cells growth as well as prostatosphere formation [ 91 , 92 ].…”