Background:U2AF homology motif kinase 1(UHMK1)has been associated with RNA processing and protein phosphorylation,thereby influencing tumor progression.The study aimed to explore its regulatory mechanisms and biologic...Background:U2AF homology motif kinase 1(UHMK1)has been associated with RNA processing and protein phosphorylation,thereby influencing tumor progression.The study aimed to explore its regulatory mechanisms and biological functions in human prostate cancer(PCa).Methods:In this study,we systematically evaluated the expression and prognostic significance of UHMK1 in public databases,followed by validation through immunohis-tochemistry(IHC)in PCa specimens.Both gain-of-function and loss-of-function experiments were conducted to elucidate the role of UHMK1 in vitro and in vivo.Additionally,a series of molecular and biochemical assays were performed to investigate the regulatory mechanisms underlying UHMK1 activity.Results:Our findings revealed that UHMK1 expression was significantly upregulated in PCa tissues and correlated with poor patient prognosis,as demonstrated by analysis of public datasets and confirmed by immunohistochemical staining.Functional studies showed that UHMK1 depletion suppressed tumor cell proliferation and metastasis,while its overexpression promoted these processes.Mechanistically,we identified that UHMK1 phosphorylates nuclear receptor coactivator 3(NCOA3),which subsequently activates activating transcription factor 4(ATF4)to upregulate methylenetetrahydrofolate dehy-drogenase 2(MTHFD2)transcription.Interestingly,MTHFD2 was found to reciprocally enhance UHMK1 expression,establishing a positive feedback loop.Conclusions:In conclusion,our data suggest that the UHMK1-MTHFD2 axis forms a positive feedback loop that drives PCa progression.Targeting this loop represents a promising therapeutic strategy for restraining prostate cancer development and progression.展开更多
亚甲基四氢叶酸还原酶2 (Methylenetetrahydrofolate dehydrogenase 2, MTHFD2)是一种参与叶酸代谢的四甲基叶酸脱氢酶,主要位于线粒体内,在一碳代谢过程中催化亚甲基四氢叶酸成甲酰基四氢叶酸。MTHFD2在恶性肿瘤组织中表达上调,在正常...亚甲基四氢叶酸还原酶2 (Methylenetetrahydrofolate dehydrogenase 2, MTHFD2)是一种参与叶酸代谢的四甲基叶酸脱氢酶,主要位于线粒体内,在一碳代谢过程中催化亚甲基四氢叶酸成甲酰基四氢叶酸。MTHFD2在恶性肿瘤组织中表达上调,在正常组织中几乎不表达,在肿瘤代谢重编程中发挥重要作用,通过AKT、JAK/STAT等信号通路调控代谢,影响细胞一碳代谢、有氧糖酵解,以适应快速增值的细胞所需要的物质,多数证据都表明其与肿瘤的发生、预后有着密切的关系,并将其作为预后标志物或潜在的治疗靶点。目前MTHFD2在人类恶性肿瘤中的代谢作用机制尚未明确,未来深入研究MTHFD2在肿瘤代谢重编程与信号通路的关系及其作为肿瘤治疗靶标的作用,可为恶性肿瘤的治疗提供新决策。Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is an enzyme involved in folate metabolism, primarily located in the mitochondria. It catalyzes the conversion of methylenetetrahydrofolate to formyltetrahydrofolate during one-carbon metabolism. MTHFD2 is upregulated in malignant tumors and is almost not expressed in normal tissues, playing a significant role in tumor metabolic reprogramming. It regulates metabolism through signaling pathways such as AKT and JAK/STAT, affecting cellular one-carbon metabolism and aerobic glycolysis to accommodate the needs of rapidly proliferating cells. Most evidence suggests a close relationship between MTHFD2 expression and tumor development and prognosis, making it a potential prognostic marker or therapeutic target. Currently, the mechanisms of MTHFD2’s metabolic roles in human malignancies are not well understood. Future in-depth studies on the relationship between MTHFD2 in tumor metabolic reprogramming and signaling pathways, and its role as a therapeutic target, could provide new decisions for the treatment of malignant tumors.展开更多
Folate metabolism plays an essential role in tumor development.Various cancers display therapeutic response to reagents targeting key enzymes of the folate cycle,but obtain chemoresistance later.Therefore,novel target...Folate metabolism plays an essential role in tumor development.Various cancers display therapeutic response to reagents targeting key enzymes of the folate cycle,but obtain chemoresistance later.Therefore,novel targets in folate metabolism are highly demanded.Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2(MTHFD2)is one of the key enzymes in folate metabolism and its expression is highly increased in mutiple human cancers.However,the underlying mechanism that regulates MTHFD2 expression remains unknown.Here,we elucidate that SIRT4 deacetylates the conserved lysine 50(K50)residue in MTHFD2.K50 deacetylation destabilizes MTHFD2 by elevating cullin 3 E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation,leading to suppression of nicotinamide adenine dinucleotide phosphate production in tumor cells and accumulation of intracellular reactive oxygen species,which in turn inhibits the growth of breast cancer cells.Collectively,our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability,bridging nutrient/folate stress and cellular redox to act on cancer cell growth.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81902617 and 82100816)Guangdong Natural Science Foundation(Grant No.2021A1515012322)Guangzhou Basic and Applied Basic Research Subject-Young Doctor’s“Sailing”Project(Grant No.2024A04J4702).
文摘Background:U2AF homology motif kinase 1(UHMK1)has been associated with RNA processing and protein phosphorylation,thereby influencing tumor progression.The study aimed to explore its regulatory mechanisms and biological functions in human prostate cancer(PCa).Methods:In this study,we systematically evaluated the expression and prognostic significance of UHMK1 in public databases,followed by validation through immunohis-tochemistry(IHC)in PCa specimens.Both gain-of-function and loss-of-function experiments were conducted to elucidate the role of UHMK1 in vitro and in vivo.Additionally,a series of molecular and biochemical assays were performed to investigate the regulatory mechanisms underlying UHMK1 activity.Results:Our findings revealed that UHMK1 expression was significantly upregulated in PCa tissues and correlated with poor patient prognosis,as demonstrated by analysis of public datasets and confirmed by immunohistochemical staining.Functional studies showed that UHMK1 depletion suppressed tumor cell proliferation and metastasis,while its overexpression promoted these processes.Mechanistically,we identified that UHMK1 phosphorylates nuclear receptor coactivator 3(NCOA3),which subsequently activates activating transcription factor 4(ATF4)to upregulate methylenetetrahydrofolate dehy-drogenase 2(MTHFD2)transcription.Interestingly,MTHFD2 was found to reciprocally enhance UHMK1 expression,establishing a positive feedback loop.Conclusions:In conclusion,our data suggest that the UHMK1-MTHFD2 axis forms a positive feedback loop that drives PCa progression.Targeting this loop represents a promising therapeutic strategy for restraining prostate cancer development and progression.
文摘亚甲基四氢叶酸还原酶2 (Methylenetetrahydrofolate dehydrogenase 2, MTHFD2)是一种参与叶酸代谢的四甲基叶酸脱氢酶,主要位于线粒体内,在一碳代谢过程中催化亚甲基四氢叶酸成甲酰基四氢叶酸。MTHFD2在恶性肿瘤组织中表达上调,在正常组织中几乎不表达,在肿瘤代谢重编程中发挥重要作用,通过AKT、JAK/STAT等信号通路调控代谢,影响细胞一碳代谢、有氧糖酵解,以适应快速增值的细胞所需要的物质,多数证据都表明其与肿瘤的发生、预后有着密切的关系,并将其作为预后标志物或潜在的治疗靶点。目前MTHFD2在人类恶性肿瘤中的代谢作用机制尚未明确,未来深入研究MTHFD2在肿瘤代谢重编程与信号通路的关系及其作为肿瘤治疗靶标的作用,可为恶性肿瘤的治疗提供新决策。Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is an enzyme involved in folate metabolism, primarily located in the mitochondria. It catalyzes the conversion of methylenetetrahydrofolate to formyltetrahydrofolate during one-carbon metabolism. MTHFD2 is upregulated in malignant tumors and is almost not expressed in normal tissues, playing a significant role in tumor metabolic reprogramming. It regulates metabolism through signaling pathways such as AKT and JAK/STAT, affecting cellular one-carbon metabolism and aerobic glycolysis to accommodate the needs of rapidly proliferating cells. Most evidence suggests a close relationship between MTHFD2 expression and tumor development and prognosis, making it a potential prognostic marker or therapeutic target. Currently, the mechanisms of MTHFD2’s metabolic roles in human malignancies are not well understood. Future in-depth studies on the relationship between MTHFD2 in tumor metabolic reprogramming and signaling pathways, and its role as a therapeutic target, could provide new decisions for the treatment of malignant tumors.
基金supported by the National Key R&D Program of China(2020YFA0803400/2020YFA0803402 and 2019YFA0801703 to Q.-Y.L.)the National Natural Science Foundation of China(81872240 to M.Y.,82002951 to J.L,and 81790250/81790253,91959202,and 82121004 to Q.-Y.L.)the Innovation Program of Shanghai Municipal Education Commission(N173606 to Q.-Y.L.).
文摘Folate metabolism plays an essential role in tumor development.Various cancers display therapeutic response to reagents targeting key enzymes of the folate cycle,but obtain chemoresistance later.Therefore,novel targets in folate metabolism are highly demanded.Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2(MTHFD2)is one of the key enzymes in folate metabolism and its expression is highly increased in mutiple human cancers.However,the underlying mechanism that regulates MTHFD2 expression remains unknown.Here,we elucidate that SIRT4 deacetylates the conserved lysine 50(K50)residue in MTHFD2.K50 deacetylation destabilizes MTHFD2 by elevating cullin 3 E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation,leading to suppression of nicotinamide adenine dinucleotide phosphate production in tumor cells and accumulation of intracellular reactive oxygen species,which in turn inhibits the growth of breast cancer cells.Collectively,our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability,bridging nutrient/folate stress and cellular redox to act on cancer cell growth.
