m6A Target Gene Information

General Information of the m6A Target Gene (ID: M6ATAR00260)
Target Name Forkhead box protein O3 (FOXO3)
Synonyms
AF6q21 protein; Forkhead in rhabdomyosarcoma-like 1; FKHRL1; FOXO3A
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Gene Name FOXO3
Chromosomal Location 6q21
Function
Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy. Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation. In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3.
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Gene ID 2309
Uniprot ID
FOXO3_HUMAN
HGNC ID
HGNC:3821
Ensembl Gene ID
ENSG00000118689
KEGG ID
hsa:2309
Full List of m6A Methylation Regulator of This Target Gene and Corresponding Disease/Drug Response(s)
FOXO3 can be regulated by the following regulator(s), and cause disease/drug response(s). You can browse detail information of regulator(s) or disease/drug response(s).
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YTH domain-containing family protein 1 (YTHDF1) [READER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by YTHDF1
Cell Line AGS cell line Homo sapiens
Treatment: shYTHDF1 AGS
Control: shNC AGS
 GSE166972
Regulation
logFC: 1.07E+00
p-value: 3.17E-02
More Results Click to View More RNA-seq Results
Representative RIP-seq result supporting the interaction between FOXO3 and the regulator
Cell Line Hela Homo sapiens
Regulation logFC: 2.44E+00 GSE63591
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Target Regulation Up regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
Methyltransferase-like 14 (METTL14) [WRITER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by METTL14
Cell Line MDA-MB-231 Homo sapiens
Treatment: siMETTL14 MDA-MB-231 cells
Control: MDA-MB-231 cells
 GSE81164
Regulation
logFC: -1.48E+00
p-value: 5.68E-29
More Results Click to View More RNA-seq Results
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [2]
Response Summary Global RNA m6A methylation and METTL14 expression were significantly increased in placental tissues obtained from patients with preeclampsia. Forkhead box protein O3 (FOXO3) inhibition effectively prevented the impairment of trophoblast proliferation and invasion, and diminished the induction of trophoblast autophagy and apoptosis in METTL14-overexpressing HTR-8/SVneo cells.
Target Regulation Up regulation
Responsed Disease Pre-eclampsia ICD-11: JA24
 Disease Info 
Cell Process Cell autophagy
In-vitro Model HTR-8/SVneo Normal Homo sapiens CVCL_7162
HTR-8 Normal Homo sapiens CVCL_D728
Methyltransferase-like 3 (METTL3) [WRITER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by METTL3
Cell Line mouse embryonic stem cells Mus musculus
Treatment: METTL3-/- ESCs
Control: Wild type ESCs
 GSE145309
Regulation
logFC: 8.00E-01
p-value: 1.28E-68
More Results Click to View More RNA-seq Results
In total 2 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [3]
Response Summary METTL3 and Forkhead box protein O3 (FOXO3) levels are tightly correlated in hepatocellular carcinoma patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6 A-dependent sorafenib sensitivity.
Target Regulation Down regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell Transport
Cell catabolism
Cell autophagy
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
HUVEC-C Normal Homo sapiens CVCL_2959
WRL 68 Endocervical adenocarcinoma Homo sapiens CVCL_0581
In-vivo Model For the drug-resistant subcutaneous tumor models, drug administration was adopted when the tumors reached about 50 mm3 in size, at which point mice were randomized for treatment with DMSO(intraperitoneally) or sorafenib (50 mg/kg/every 2 days, intraperitoneally). For the patient-derived tumor xenograft model, drug administration began 4 weeks after tumors reached about 100 mm3 in size with sorafenib (50 mg/kg/every 3 days, intraperitoneally) or siCtrl/siMETTL3 intratumor injection.
Experiment 2 Reporting the m6A Methylation Regulator of This Target Gene [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Target Regulation Up regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
RNA demethylase ALKBH5 (ALKBH5) [ERASER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by ALKBH5
Cell Line 143B cell line Homo sapiens
Treatment: siALKBH5 transfected 143B cells
Control: siControl 143B cells
 GSE154528
Regulation
logFC: -1.05E+00
p-value: 3.53E-06
More Results Click to View More RNA-seq Results
In total 2 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [4]
Response Summary ALKBH5 plays an antitumor role in colorectal cancer by modulating the Forkhead box protein O3 (FOXO3)/miR-21/SPRY2 axis, which not only suggests a regulatory effect between ALKBH5 and FOXO3, but also provides a new therapeutic direction for colorectal cancer.
Target Regulation Down regulation
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Pathway Response FoxO signaling pathway hsa04068
In-vitro Model Caco-2 Colon adenocarcinoma Homo sapiens CVCL_0025
FHC Normal Homo sapiens CVCL_3688
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 Colon adenocarcinoma Homo sapiens CVCL_0547
Experiment 2 Reporting the m6A Methylation Regulator of This Target Gene [5]
Response Summary ALKBH5 was upregulated in the cardiomyocytes of diabetic cardiomyopathy mice and posttranscriptionally activated Forkhead box protein O3 (FOXO3) by m6A demethylation in an m6A-YTHDF2-dependent manner.This work reveals the key function of the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway in DCM and provides insight into the critical roles of m6A methylation in DCM.
Target Regulation Up regulation
Responsed Disease Diabetic cardiomyopathy ICD-11: BC43.7
 Disease Info 
Pathway Response Hippo signaling pathway hsa04390
FoxO signaling pathway hsa04068
Cell Process Cell apoptosis
In-vitro Model Neonatal rat ventricular cardiomyocytes (Primary myocyte cells)
In-vivo Model The model mice were intraperitoneally injected with streptozotocin (STZ; Sigma-Aldrich Corp., USA). The dose of STZ was 50 mg/kg for 5 days. 7 days after the last injection, blood glucose concentrations were recorded. Mouse models of diabetes were considered established when fasting blood glucose concentrations reached >11.1 mmol/L, and body weight was measured.
YTH domain-containing family protein 3 (YTHDF3) [READER]
 Regulator Info 
Representative RIP-seq result supporting the interaction between FOXO3 and the regulator
Cell Line Hela Homo sapiens
Regulation logFC: 2.93E+00 GSE86214
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [6]
Response Summary YTHDF3 as a negative regulator of antiviral immunity through the translational promotion of Forkhead box protein O3 (FOXO3) mRNA under homeostatic conditions, adding insight into the networks of RNA-binding protein-RNA interactions in homeostatically maintaining host antiviral immune function and preventing inflammatory response.
Target Regulation Up regulation
Responsed Disease Inflammatory response ICD-11: MG46
 Disease Info 
Pathway Response FoxO signaling pathway hsa04068
In-vivo Model YTHDF3-/- mice were generated using the CRISPR-Cas9 system.
Colorectal cancer [ICD-11: 2B91]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [4]
Response Summary ALKBH5 plays an antitumor role in colorectal cancer by modulating the Forkhead box protein O3 (FOXO3)/miR-21/SPRY2 axis, which not only suggests a regulatory effect between ALKBH5 and FOXO3, but also provides a new therapeutic direction for colorectal cancer.
Responsed Disease Colorectal cancer [ICD-11: 2B91]
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response FoxO signaling pathway hsa04068
In-vitro Model Caco-2 Colon adenocarcinoma Homo sapiens CVCL_0025
FHC Normal Homo sapiens CVCL_3688
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 Colon adenocarcinoma Homo sapiens CVCL_0547
Liver cancer [ICD-11: 2C12]
 Disease Info 
In total 3 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [3]
Response Summary METTL3 and Forkhead box protein O3 (FOXO3) levels are tightly correlated in hepatocellular carcinoma patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6 A-dependent sorafenib sensitivity.
Responsed Disease Hepatocellular carcinoma [ICD-11: 2C12.02]
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell Transport
Cell catabolism
Cell autophagy
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
HUVEC-C Normal Homo sapiens CVCL_2959
WRL 68 Endocervical adenocarcinoma Homo sapiens CVCL_0581
In-vivo Model For the drug-resistant subcutaneous tumor models, drug administration was adopted when the tumors reached about 50 mm3 in size, at which point mice were randomized for treatment with DMSO(intraperitoneally) or sorafenib (50 mg/kg/every 2 days, intraperitoneally). For the patient-derived tumor xenograft model, drug administration began 4 weeks after tumors reached about 100 mm3 in size with sorafenib (50 mg/kg/every 3 days, intraperitoneally) or siCtrl/siMETTL3 intratumor injection.
Experiment 2 Reporting the m6A-centered Disease Response [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Responsed Disease Hepatocellular carcinoma [ICD-11: 2C12.02]
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
Experiment 3 Reporting the m6A-centered Disease Response [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Responsed Disease Hepatocellular carcinoma [ICD-11: 2C12.02]
Target Regulator YTH domain-containing family protein 1 (YTHDF1) READER
 Regulator Info 
Target Regulation Up regulation
Responsed Drug Sorafenib Approved
 Drug Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
Ovarian dysfunction [ICD-11: 5A80]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response []
Response Summary Altered m6 A modification was involved in up-regulated expression of Forkhead box protein O3 (FOXO3) mRNA in the luteinized granulosa cells from non-obese polycystic ovary syndrome patients following controlled ovarian hyperstimulation.
Responsed Disease Ovarian dysfunction [ICD-11: 5A80]
Pathway Response FoxO signaling pathway hsa04068
In-vitro Model ()
Cardiomyopathy [ICD-11: BC43]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [5]
Response Summary ALKBH5 was upregulated in the cardiomyocytes of diabetic cardiomyopathy mice and posttranscriptionally activated Forkhead box protein O3 (FOXO3) by m6A demethylation in an m6A-YTHDF2-dependent manner.This work reveals the key function of the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway in DCM and provides insight into the critical roles of m6A methylation in DCM.
Responsed Disease Diabetic cardiomyopathy [ICD-11: BC43.7]
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Hippo signaling pathway hsa04390
FoxO signaling pathway hsa04068
Cell Process Cell apoptosis
In-vitro Model Neonatal rat ventricular cardiomyocytes (Primary myocyte cells)
In-vivo Model The model mice were intraperitoneally injected with streptozotocin (STZ; Sigma-Aldrich Corp., USA). The dose of STZ was 50 mg/kg for 5 days. 7 days after the last injection, blood glucose concentrations were recorded. Mouse models of diabetes were considered established when fasting blood glucose concentrations reached >11.1 mmol/L, and body weight was measured.
Pre-eclampsia [ICD-11: JA24]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [2]
Response Summary Global RNA m6A methylation and METTL14 expression were significantly increased in placental tissues obtained from patients with preeclampsia. Forkhead box protein O3 (FOXO3) inhibition effectively prevented the impairment of trophoblast proliferation and invasion, and diminished the induction of trophoblast autophagy and apoptosis in METTL14-overexpressing HTR-8/SVneo cells.
Responsed Disease Pre-eclampsia [ICD-11: JA24]
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Up regulation
Cell Process Cell autophagy
In-vitro Model HTR-8/SVneo Normal Homo sapiens CVCL_7162
HTR-8 Normal Homo sapiens CVCL_D728
Inflammatory response [ICD-11: MG46]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [6]
Response Summary YTHDF3 as a negative regulator of antiviral immunity through the translational promotion of Forkhead box protein O3 (FOXO3) mRNA under homeostatic conditions, adding insight into the networks of RNA-binding protein-RNA interactions in homeostatically maintaining host antiviral immune function and preventing inflammatory response.
Responsed Disease Inflammatory response [ICD-11: MG46]
Target Regulator YTH domain-containing family protein 3 (YTHDF3) READER
 Regulator Info 
Target Regulation Up regulation
Pathway Response FoxO signaling pathway hsa04068
In-vivo Model YTHDF3-/- mice were generated using the CRISPR-Cas9 system.
Sorafenib [Approved]
 Drug Info 
In total 3 item(s) under this drug
Experiment 1 Reporting the m6A-centered Drug Response [3]
Response Summary METTL3 and Forkhead box protein O3 (FOXO3) levels are tightly correlated in hepatocellular carcinoma patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6 A-dependent sorafenib sensitivity.
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell Transport
Cell catabolism
Cell autophagy
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
Hepa 1-6 Hepatocellular carcinoma of the mouse Mus musculus CVCL_0327
Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
HUVEC-C Normal Homo sapiens CVCL_2959
WRL 68 Endocervical adenocarcinoma Homo sapiens CVCL_0581
In-vivo Model For the drug-resistant subcutaneous tumor models, drug administration was adopted when the tumors reached about 50 mm3 in size, at which point mice were randomized for treatment with DMSO(intraperitoneally) or sorafenib (50 mg/kg/every 2 days, intraperitoneally). For the patient-derived tumor xenograft model, drug administration began 4 weeks after tumors reached about 100 mm3 in size with sorafenib (50 mg/kg/every 3 days, intraperitoneally) or siCtrl/siMETTL3 intratumor injection.
Experiment 2 Reporting the m6A-centered Drug Response [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
Experiment 3 Reporting the m6A-centered Drug Response [1]
Response Summary METTL3 can sensitise hepatocellular carcinoma cells to sorafenib through stabilising Forkhead box protein O3 (FOXO3) in an m6A-dependent manner and translated by YTHDF1, thereby inhibiting the transcription of autophagy-related genes, including ATG3, ATG5, ATG7, ATG12, and ATG16L1.
Target Regulator YTH domain-containing family protein 1 (YTHDF1) READER
 Regulator Info 
Target Regulation Up regulation
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12.02
 Disease Info 
Pathway Response FoxO signaling pathway hsa04068
Cell Process Cell autophagy
References
Ref 1 RNA N6-methyladenosine: a new player in autophagy-mediated anti-cancer drug resistance. Br J Cancer. 2021 May;124(10):1621-1622. doi: 10.1038/s41416-021-01314-z. Epub 2021 Mar 15.
Ref 2 Upregulation of METTL14 contributes to trophoblast dysfunction by elevating FOXO3a expression in an m(6)A-dependent manner. Placenta. 2022 Jun 24;124:18-27. doi: 10.1016/j.placenta.2022.05.008. Epub 2022 May 14.
Ref 3 RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J. 2020 Jun 17;39(12):e103181. doi: 10.15252/embj.2019103181. Epub 2020 May 5.
Ref 4 m(6)A demethylase ALKBH5 inhibits cell proliferation and the metastasis of colorectal cancer by regulating the FOXO3/miR-21/SPRY2 axis. Am J Transl Res. 2021 Oct 15;13(10):11209-11222. eCollection 2021.
Ref 5 CircRNA CDR1as promotes cardiomyocyte apoptosis through activating hippo signaling pathway in diabetic cardiomyopathy. Eur J Pharmacol. 2022 May 5;922:174915. doi: 10.1016/j.ejphar.2022.174915. Epub 2022 Mar 24.
Ref 6 RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation. Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):976-981. doi: 10.1073/pnas.1812536116. Epub 2018 Dec 27.