Transcriptional impact of MTHFD2 in Human Aortic Endothelial Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100261 | GEO | 2018/06/19
REPOSITORIES: GEO
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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.
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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.
2019-07-02 | GSE84007 | GEO
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.
2016-06-06 | GSE81062 | GEO
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.
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Project description:Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the molecular mechanisms linked to hyperactivation of Wnt/β-catenin signaling and the strategy for targeting this pathway in HCC are incompletely understood. In this study, a screen of the potential kinases regulating Wnt/β-catenin signaling revealed that NME7 is a positive regulator of this pathway. NME7 was upregulated in HCC, and its expression was positively correlated with the clinical features of patients with HCC. Knockdown of NME7 inhibited the growth and tumorigenesis of HCC cells, while overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model of HCC established by hydrodynamic injection and promote the growth of tumor-derived organoids. Mechanistically, GSK3β was identified as the substrate of NME7, and their interaction was strengthened upon Wnt3a stimulation. NME7 exerts protein kinase activity and phosphorylates serine 9 of GSK3β in vitro and in vivo. Through further study, MTHFD2, the key enzyme in one-carbon metabolism, was found to be the target gene of β-catenin and to mediate the biological functions of NME7. Moreover, mouse tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to the MTHFD2 inhibitor LY345899. Additionally, the expression levels of NME7, β-catenin and MTHFD2 correlated well in HCC, and higher expression of all three predicted poor prognosis. Taken together, the results of this study emphasize the crucial roles of NME7 protein kinase activity in activating one-carbon metabolism and Wnt/β-catenin signaling, suggesting that NME7 and MTHFD2 are therapeutic targets for HCC.
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Project description:Conducted proteomics on samples from patients with aortic aneurysm and from non-dilated controls. Furthermore, we investigated both patients with bicuspid aortic valves (BAV) and also the more normal tricuspid aortic valves (TAV). The aim was to elucidate the molecular mechanisms behind the higher propensity of BAV patients to develop aorta dilation and consequent aortic aneurysm.
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Project description:Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B-cell lymphomas. How EBV remodels metabolic pathways to support rapid B-cell outgrowth remains largely unknown. To gain insights, primary human B-cells were profiled by tandem-mass-tag based proteomics at rest and at 9 time points after infection. >8000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 1C enzyme MTHFD2, which played key roles in EBV-driven B-cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B-cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism.
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