FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

Sakaguchi, Masaji; Cai, Weikang; Wang, Chih-Hao; Cederquist, Carly; Damasio, Marcos; Homan, Erica P.; Batista, Thiago M.; Ramirez, Alfred K.; Gupta, Manoj; Steger, Martin; Albrechtsen, Nicolai J. Wewer; Singh, Shailendra Kumar; Araki, Eiichi; Mann, Matthias; Enerbäck, Sven; Kahn, C. Ronald

doi:10.1038/s41467-019-09418-0

Cited by 76 publications

(97 citation statements)

References 60 publications

(61 reference statements)

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“…After FOXK2 knockdown, we found that proliferation of GCs was inhibited and the numbers of apoptotic cells were increased. A similar result was reported in liver cells (Sakaguchi et al, 2019).…”

Section: Discussionsupporting

confidence: 89%

“…A recent study linked FOXK2 to regulation of liver cellular proliferation and apoptosis via the PI3K-Akt pathway (Sakaguchi et al, 2019). In this study, we examined the role of FOXK2 knockdown on chicken GC proliferation and apoptosis.…”

Section: Foxk2 Promotes Granulosa Cell Proliferation Via Another Pi3kmentioning

confidence: 98%

“…Previous research reported that FoxKs translocation to the nucleus is dependent on the PI3K-Akt-mTOR pathway (Sakaguchi et al, 2019). To further explore the role of FOXK2 in the PI3K signaling pathway, a PI3K inhibitor (LY294002) and activator (740Y-P) were used.…”

Section: Foxk2 Promotes Granulosa Cell Proliferation Via Another Pi3kmentioning

confidence: 99%

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High Expression of miR-204 in Chicken Atrophic Ovaries Promotes Granulosa Cell Apoptosis and Inhibits Autophagy

Cui

Liu

Amevor

et al. 2020

Front. Cell Dev. Biol.

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Chicken atrophic ovaries have decreased volume and are indicative of ovarian failure, presence of a tumor, or interrupted ovarian blood supply. Ovarian tumor is accompanied by an increase in follicular atresia, granulosa cell (GC) apoptosis, and autophagy. In a previous study, we found using high throughput sequencing that miR-204 is highly expressed in chicken atrophic ovaries. Thus, in the present study, we further investigated its function in GC apoptosis and autophagy. We found that overexpression of miR-204 reduced mRNA and protein levels of proliferation-related genes and increased apoptosis-related genes. Cell counting kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), and flow cytometry assays revealed that miR-204 inhibited GC proliferation and promoted apoptosis. Furthermore, we confirmed with reporter gene assays that Forkhead box K2 (FOXK2) was directly targeted by miR-204. FOXK2, as a downstream regulator of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathways, promoted GC proliferation and inhibited apoptosis. Subsequently, we observed that miR-204 was involved in GC autophagy by targeting Transient Receptor Potential Melastatin 3 (TRPM3). The luciferase activities of the two binding sites of TRPM3 were decreased in response to treatment with a miR-204 mimic, and the autophagic flux was increased after miR-204 inhibition. However, overexpression of miR-204 had opposite results in autophagosomes and autolysosomes. miR-204 inhibits GC autophagy by suppressing the protein expression of TRPM3/AMP-activated protein kinase (AMPK)/ULK signaling pathway components. Inhibition of miR-204 enhanced autophagy by accumulating and degrading the protein levels of LC3-II (Microtubule Associated Protein Light Chain 3B) and p62 (Protein of 62 kDa), respectively, whereas miR-204 overexpression was associated with contrary results. Immunofluorescence staining showed that there was a significant reduction in the fluorescent intensity of LC3B, whereas p62 protein was increased after TRPM3 silencing. Collectively, our results indicate that miR-204 is highly expressed in chicken atrophic ovaries, which promotes GC apoptosis via repressing FOXK2 through the PI3K/AKT/mTOR pathway and inhibits autophagy by impeding the TRPM3/AMPK/ULK pathway.

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Section: Discussionsupporting

confidence: 89%

Section: Foxk2 Promotes Granulosa Cell Proliferation Via Another Pi3kmentioning

confidence: 98%

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High Expression of miR-204 in Chicken Atrophic Ovaries Promotes Granulosa Cell Apoptosis and Inhibits Autophagy

Cui

Liu

Amevor

et al. 2020

Front. Cell Dev. Biol.

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“…It is made depletion of the motifs for Nr1i3 and Pit1, both of which are not expressed in human brain (Supplemental Figure 8c) [67,68]. When interpreting the multi-species liver model, in addition to the motifs that we found for the model trained on mouse sequences, we also found the motifs for additional TFs that are known to be involved in the liver, including Hnf4a [83][84][85], Foxk1 [86,87], Ets2 [88,89], Sp1 [90,91], Onecut1 [92,93], Bcl6 [94,95], and Nfe2l2 [96,97], as well as a depletion of the motif for Dbx1, which is not expressed in human liver [67,68], and a depletion of the motif for Zfp637 (Supplemental Figure 8d).…”

Section: Conservation Scoresmentioning

confidence: 84%

Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin

Kaplow

Schäffer

Wirthlin

et al. 2020

Preprint

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Many phenotypes have evolved through gene expression, meaning that differences between species are caused in part by differences in enhancers. Here, we demonstrate that we can accurately predict differences between species in open chromatin status at putative enhancers using machine learning models trained on genome sequence across species. We present a new set of criteria that we designed to explicitly demonstrate if models are useful for studying open chromatin regions whose orthologs are not open in every species. Our approach and evaluation metrics can be applied to any tissue or cell type with open chromatin data available from multiple species.

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“…The balance of FOXO and FOXM1 transcription factors integrates Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mediated metabolic status and cell cycle regulation through competitive regulation of target genes (including Insulin-like growth factor-1 (IGF1)) in neonatal cardiomyocytes (11). FOXK1 and FOXK2 are important in the regulation of mitochondrial function, metabolism and apoptosis (12). FOXO family facilitated the cellular antioxidant defense, and on the other hand, ROS may regulate FOXO activity at many levels (13).…”

Section: Introductionmentioning

confidence: 99%

FOXC1 Promotes HCC Proliferation and Metastasis by Upregulating DNMT3B to Induce DNA Hypermethylation of CTH Promoter

Lin

Huang

et al. 2020

Preprint

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Background: Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC.Methods: We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo, we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts.Results: Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell proliferation, invasion and metastasis caused by the inhibition of FOXC1 could be reversed by knockdown of CTH. Meanwhile, FOXC1 upregulated de novo DNA methylase 3B (DNMT3B) expression to induce DNA hypermethylation of CTH promoter, which resulted in low expression of CTH in HCC cells. Moreover, low levels of ROS induced by N-acetylcysteine (NAC) which is an antioxidant inhibited the cell proliferation, migration, and invasion abilities mediated by FOXC1 overexpression, whereas high levels of ROS induced by L-Buthionine-sulfoximine (BSO) rescued the suppression results mediated by FOXC1 knockdown. Our study demonstrated that the overexpression of FOXC1 that was induced by the ROS dependent on the extracellular regulated protein kinases 1 and 2 (ERK1/2)- phospho-ETS Transcription Factor 1 (p-ELK1) pathway. In human HCC tissues, FOXC1 expression was positively correlated with oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), p-ELK1 and DNMT3B expression, but negatively correlated with CTH expression. HCC patients with positive co-expression of 8-OHdG/FOXC1 or p-ELK1/FOXC1 or FOXC1/DNMT3B had the worst prognosis, whereas HCC patients who had positive FOXC1 and negative CTH expression exhibited the worst prognosis. Conclusion: In a word, we clarify that the positive feedback loop of ROS-FOXC1-cysteine metabolism-ROS is important for promoting liver cancer proliferation and metastasis, and this pathway may provide a prospective clinical treatment approach for HCC.

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FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

Cited by 76 publications

References 60 publications

High Expression of miR-204 in Chicken Atrophic Ovaries Promotes Granulosa Cell Apoptosis and Inhibits Autophagy

High Expression of miR-204 in Chicken Atrophic Ovaries Promotes Granulosa Cell Apoptosis and Inhibits Autophagy

Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin

FOXC1 Promotes HCC Proliferation and Metastasis by Upregulating DNMT3B to Induce DNA Hypermethylation of CTH Promoter

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