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Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression

ABSTRACT: Subcellular compartmentalization of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we reveal that, in cancer cells, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localizes in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces centromere overexpression and severe methylation defects, and impedes correct mitosis completion. As a consequence, MTHFD2 deficient cells accumulate chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, attributing to nuclear MTHFD2 an enzymatic active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, and emphasizes that cancer metabolism rewiring may encompass the relocation of metabolic enzymes to alternative subcellular compartments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232307 | GEO | 2024/07/26

REPOSITORIES: GEO

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Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression [RNA-seq]

Project description:Subcellular compartmentalization of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we reveal that, in cancer cells, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localizes in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces centromere overexpression and severe methylation defects, and impedes correct mitosis completion. As a consequence, MTHFD2 deficient cells accumulate chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, attributing to nuclear MTHFD2 an enzymatic active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, and emphasizes that cancer metabolism rewiring may encompass the relocation of metabolic enzymes to alternative subcellular compartments.

2024-07-26 | GSE230750 | GEO

Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression

Project description:Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression

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Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression

Project description:Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression

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Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression [RNA-seq]

Project description:Nuclear MTHFD2 secures centromere methylation, chromosome stability and correct mitosis progression [RNA-seq]

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Transcriptional impact of MTHFD2 in Human Aortic Endothelial Cells

Project description:We performed transcriptome analysis of Human Aortic Endothelial Cells after siRNA mediated knockdown of MTHFD2. We identified MTHFD2 as a key driver for a gene cluster which integrates mitochondrial one-carbon metabolism, serine synthesizing enzymes as well as common amino acid and ER stress response genes.

2018-06-19 | GSE100261 | GEO

Knock down of MTHFD2 of lung adenocarcinoma cell line H322

Project description:Lung cancer is leading cause of cancer-related death in the world, because of high recurrence rate and acquired resistance to targeting drugs such as gefitinib. Here we uncover a critical MTHFD2 enzyme-mediated purine synthesis pathway in mitochondria in poor prognostic lung cancer. Expression of MTHFD2 was induced by epidermal growth factor (EGF) stimulation. It was overexpressed in gefitinib-resistant cancer cells and high-grade tumor tissues. Knockdown of MTHFD2 significantly decreased not only in vitro and in vivo cell growth but also tumor sphere formation and tumor initiating activity, properties of cancer stem-like cells. Integrated analysis of metabolome and transcriptome of MTHFD2 knocked-down cells revealed significant accumulation of the nucleotide intermediates before MTHFD2-mediated one carbon transfer and marked deficiency of purine nucleotides required for cell growth. Thus we provide evidence that MTHFD2 pathway is critical for growth of both cancer cells and cancer stem-like cells as an Achilles heel to eradicate tumors in poor prognostic lung cancer.

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Targeting MTHFD2 in Acute Myeloid Leukemia

Project description:Purpose: Identify new targets in acute myeloid leukemia (AML). Methods: MOLM-14 cells were transduced with lentivirus encoding shRNAs targeting MTHFD2 (shMTHFD2 hairpin TRCN0000036553, denoted M5) and control (LacZ, shControl TRCN0000072231). RNA from 6 samples, biological duplicates (LacZ1, LacZ2; M5-1, M5-2) and a technical replicate (LacZ3, M5-3) were sequenced as 50+50 bp paired-end reads using Illumina TruSeq strand specific library. The pool of six samples was sequenced on two lanes of an Illumina HiSeq, generating 101bp paired end reads. The software package RSEM (Li et al., 2001) was run using Bowtie (version 1.0.0) to align the reads that passed quality filters to the hg19 GENCODE version 17 (http://www.gencodegenes.org/releases/17.html) transcriptome and to quantify transcript abundance at isoform and gene level. Results: MTHFD2 suppression induces AML differentiation. There was upregulation of well-validated myeloid differentiation genes and gene sets consistent with myeloid maturation. Conclusion: Our study supports the therapeutic targeting of MTHFD2 in AML.

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Project description:MTHFD2 is a mitochondrial enzyme within the folate cycle of one carbon metabolism. We found that MTHFD2 deficiency leads to impaired proliferation and induction of FoxP3 expression in Th17 cells and Treg cells differentiated in low TGFß conditions. Mechanistically, this occured through depleted purine pools, accumulation of purine synthesis intermediates, dampened mTORC1 activity, and altered DNA and histone methylation.

2021-11-12 | GSE180356 | GEO

Upregulation of MTHFD2 is associated with PD-L1 activation in bladder cancer via the PI3K/AKT pathway

Project description:Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors, although its exact role in bladder cancer (BC) remains to be explored. The present study determined the upregulation of MTHFD2 in BC tissues using expression data from The Cancer Genome Atlas (TCGA), a commercial BC tissue microarray (TMA) and patients’ tissues collected by surgery. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death-ligand 1 (PD-L1) expression. Next, using small interfering RNA, the expression of MTHFD2 in BC cell lines was knocked down, and the results revealed that the tumor cell proliferation and colony-formation abilities were greatly reduced, as well as the expression of PD-L1. In a xenograft nude mouse model, these findings were confirmed. Simultaneously, it was found that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA-sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression of PI3K and AKT. The activation of PI3K and AKT was enhanced after stimulation with 740Y-P, a PI3K activator, and their cellular activities and PD-L1 expression levels were restored. Finally, it was found that the MTHFD2 levels were positively correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K-AKT-targeted drugs by analyzing the Genomics of Drug Sensitivity in Cancer (GDSC) database. Overall, the present findings revealed that elevation of MTHFD2 was associated with PD-L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.

2022-11-17 | GSE217785 | GEO

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