Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages
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ABSTRACT:
PROVIDER: PRJNA281223 | ENA |
REPOSITORIES: ENA
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Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.
2017-11-30 | PXD007996 | Pride
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. This SuperSeries is composed of the SubSeries listed below.
2017-11-28 | GSE67922 | GEO
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression.
2017-11-28 | GSE67810 | GEO
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression.
2017-11-28 | GSE67808 | GEO
Project description:The goal of this study was to apply next-generation sequencing (NGS) analyses to identify genes and pathways regulated by the Foxk1 transcription factor in the liver and to see the effects of liver-specific Foxk1 deficiency in the diet-induced non-alcoholic steatohepatitis (NASH) model. Transcriptome and ChIP-seq analysis revealed that liver Foxk1 promotes the pathogenesis of NASH by regulating the expression of a series of molecules involved in hepatic lipid metabolism in an mTORC1-dependent manner.
2022-03-01 | GSE197324 | GEO
Project description:The goal of this study was to apply next-generation sequencing (NGS) analyses to identify genes and pathways regulated by the Foxk1 transcription factor in the liver and to see the effects of liver-specific Foxk1 deficiency in the diet-induced non-alcoholic steatohepatitis (NASH) model. Transcriptome and ChIP-seq analysis revealed that liver Foxk1 promotes the pathogenesis of NASH by regulating the expression of a series of molecules involved in hepatic lipid metabolism in an mTORC1-dependent manner.
2022-03-01 | GSE197322 | GEO
Project description:The goal of this study was to apply Next Generation Sequencing analyses to identify genes and pathways regulated by the FOXK1 and FOXK2 transcription factor in HeLa cells and to see whether reconstitution of FOXK1 WT and mutants can rescue the altered gene regulation in FOXK1 KO cells. Gene Ontology (GO) analysis did not uncover any dysregulated DNA damage–related pathways upon FOXKs KO. We found that cells reconstituted with any of the three FOXK1 mutants could largely rescue dysregulated gene expression in FOXK1 KO cells, similar to cells reconstituted with WT FOXK1. These suggesting that FOXK1's role in DNA damage response is not by direct transcriptional regulation of DNA damage related pathways and all the three FOXK1 mutants could not affect transcription.
2020-06-26 | GSE151029 | GEO
Project description:D3, D5 and D10 EBs from iHA-Foxk1 and Foxk1 KO cells were harvested for RNA and submitted for sequencing to understand the transcriptional profile of these cells during differentiation in the presence and absence of FOXK1
2023-05-08 | GSE202562 | GEO
Project description:50k cells from D3, D5 and D10 EBs from iHA-Foxk1 and Foxk1 KO cells were harvested for ATAC-seq and submitted for sequencing to understand the chromatin dynamics of these cells during differentiation in the presence and absence of FOXK1
2023-05-08 | GSE202517 | GEO
Project description:Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlie numerous pathologies including cancer. FOXK1 and FOXK2 (FOXK1/2) transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation. While FOXK1/2 possesses many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and often contradictory. FOXK1, but less FOXK2, is known to have oncogenic properties as higher expression levels of FOXK1 has been observed in several cancers and is correlated with tumor progression, invasion, and metastasis. However, the molecular mechanism by which FOXK1 exert its oncogenic properties in caner remains unknown. Here we show that elevated expression of FOXK1, but not FOXK2, in normal human fibroblasts promotes transcription of E2F target genes associated with increased proliferation and delayed senescence entry. Fibroblasts overexpressing FOXK1 are also more prone to cellular transformation with minimal oncogenic combinations, suggesting important oncogenic proprieties of FOXK1. Mechanistically, we found that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle and its highest levels coincides with the G1/S phase transition. Moreover, FOXK1 O-GlcNAcylation is increased following cell transformation and loss of this modification leads to decreased FOXK1 ability to promote cellular transformation and tumor growth. Cells overexpressing FOXK1 O-GlcNAcylation-defective mutants have lower E2F1 expression, cell proliferation, and tumour growth. Our results define a distinct role of FOXK1 via O-GlcNAcylation in controlling the cell cycle through the orchestration of the E2F pathway.
2024-06-10 | PXD050014 | Pride