Subcellular Trafficking of Oncoprotein FOXK1 Reverses Insulin Resistance-induced Circadian Disruption and Promotes Sensitivity of Metformin in Tumor Therapy
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ABSTRACT:
PROVIDER: PRJNA995549 | ENA |
REPOSITORIES: ENA
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Project description:The pathophysiological function of the FOXK family-member FOXK1 remains to be explored. Although tumors classically induce abnormalities in the insulin pathway, clinical trials have failed to establish insulin receptors as potential targets for tumor therapy. Metformin, so far has been identified as an effective treatment in several clinical oncology trials; however, metformin may fail to benefit all patients, and some even suffer from many side effects and drug resistance. Herein, we report that FOXK1 expression correlates with the sensitivity to metformin treatment in a variety of tumors. FOXK1 translocates into the nucleus in response to insulin stimulation and recruits multiple class I HDAC-containing complexes that regulate the expression of genes, such as PER2 and OGT, known to be critically involved in circadian rhythm and insulin resistance. Furthermore, high insulin levels associated with cancer could disturb the subcellular localization and epigenetic regulatory functions of FOXK1. Glycosylation modifications stabilize FOXK1 in the nucleus. Elevated nuclear FOXK1 competes with CLOCK for binding with BMAL1, leading to the deregulation of circadian rhythm, which, in turn, enhanced tumor cell proliferation in vitro and promoted tumor development in vivo. Correspondingly, elevated expression of nuclear FOXK1 was observed during tumor progression and was associated with a poor prognosis. Interestingly, both in vitro and in vivo experiments confirmed that cells with high FOXK1 expression were highly responsive to metformin stimulation. Collectively, these findings revealed that nuclear FOXK1 promotes tumorigenesis by disrupting circadian rhythm under insulin resistance, and its expression may serve as a potential indicator for the adjuvant treatment of tumors using metformin.
2025-07-16 | GSE237509 | 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
Project description:Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes via Foxk-Sin3-mediated transcriptional control. Examination of (1) chromatin binding of Foxk1 and Sin3A in non-starved myoblasts and (2) gene expression profiling upon either starvation or siRNA-mediated depletion of Foxk1 relative to a non-starved control.
2014-11-17 | E-GEOD-56932 | biostudies-arrayexpress
Project description:Tubular epithelial cells (TECs) undergo an energy metabolism shift from fatty acid oxidation (FAO) to glycolysis in renal fibrosis. The critical pathways leading to the halt of FAO in TECs have been well described, whereas the mechanism underlying the burst of glycolysis remains elusive. We herein reported a critical glycolysis regulator emerged in TECs amid the renal fibrosis, the transcriptional factor forkhead box protein K1 (FOXK1), which exhibited fibrogenic and metabolism-rewiring capacity. Genetic modification of FOXK1 in TECs altered the glycolytic metabolism and fibrotic lesion. The surge of a set of glycolysis-related genes following FOXK1 activation contributed to the energic shift. Nuclear-translocated FOXK1 formed condensates through liquid-liquid phase separation (LLPS) to drive the target genes transcription. The core intrinsically disordered regions (IDRs) within FOXK1 were further mapped and validated. Finally, we explored the therapeutic strategy targeting Foxk1 in the CKD mouse model by subcapsular injecting Foxk1-shRNA-carrying AAV9 vector.
2024-02-29 | GSE253528 | 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:We report DNA binding of a transcription factor Foxk1 in globle genomic DNA
2018-04-05 | GSE112709 | 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