Pällmann Nora, Deng Ke, Livgård Marte, Tesikova Martina, Jin Yixin, Frengen Nicolai Sebastian, Kahraman Nermin, Mokhlis Hamada M, Ozpolat Bulent, Kildal Wanja, Danielsen Havard Emil, Fazli Ladan, Rennie Paul S, Banerjee Partha P, Üren Aykut, Jin Yang, Kuzu Omer F, Saatcioglu Fahri
Department of Biosciences, University of Oslo, Oslo, Norway.
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
Cancer Res. 2021 Aug 1;81(15):4066-4078. doi: 10.1158/0008-5472.CAN-20-3956. Epub 2021 Jun 28.
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.
一碳（1C）代谢在具有线粒体（m1C）和细胞质（c1C）成分的代谢编程中起关键作用。我们在此表明，激活转录因子4（ATF4）仅激活前列腺癌细胞中参与m1C而非c1C循环的基因表达。这包括激活亚甲基四氢叶酸脱氢酶2（MTHFD2）的表达，其是m1C循环的核心参与者。与m1C循环在前列腺癌中的关键作用一致，MTHFD2基因敲低抑制了前列腺癌细胞的生长、前列腺球形成以及患者来源异种移植类器官的生长。此外，通过全身给药的纳米脂质体siRNA对MTHFD2进行治疗性沉默，在临床前前列腺癌小鼠模型中显著抑制了肿瘤生长。同样，MTHFD2在人类前列腺癌中的表达显著增加，基于m1C循环的基因表达特征具有显著的预后价值。此外，MTHFD2的表达受ATF4和癌蛋白c-MYC的协同调节，而c-MYC与前列腺癌有关。这些数据表明，m1C循环对前列腺癌进展至关重要，可能作为一种新型生物标志物和治疗靶点。意义：这些发现表明，线粒体而非细胞质的一碳循环在前列腺癌细胞生长和存活中起关键作用，可能作为生物标志物和/或治疗靶点。
