Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CJZ5K)

DOT Name	Forkhead box protein F1 (FOXF1)
Synonyms	Forkhead-related activator 1; FREAC-1; Forkhead-related protein FKHL5; Forkhead-related transcription factor 1
Gene Name	FOXF1
Related Disease	Adenocarcinoma ( ) Alveolar capillary dysplasia with misalignment of pulmonary veins ( ) Thyroid gland papillary carcinoma ( ) Advanced cancer ( ) Barrett esophagus ( ) Benign prostatic hyperplasia ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Carcinoma of esophagus ( ) Esophageal adenocarcinoma ( ) Familial multiple trichoepithelioma ( ) Gastrointestinal stromal tumour ( ) Mastocytosis ( ) Metastatic malignant neoplasm ( ) Neoplasm ( ) Osteosarcoma ( ) Pneumonia ( ) Pneumonitis ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary disease ( ) Pulmonary fibrosis ( ) Respiratory failure ( ) Rhabdomyosarcoma ( ) VACTERL/vater association ( ) Colorectal carcinoma ( ) Gastric cancer ( ) Lung cancer ( ) Lung carcinoma ( ) Persistent fetal circulation syndrome ( ) Stomach cancer ( ) Autism spectrum disorder ( ) Congenital diaphragmatic hernia ( ) Granular corneal dystrophy type II ( ) High blood pressure ( ) Hypoplastic left heart syndrome ( ) Intellectual disability ( ) Invasive ductal breast carcinoma ( ) Type-1 diabetes ( )
UniProt ID	FOXF1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00250
Sequence	MSSAPEKQQPPHGGGGGGGGGGGAAMDPASSGPSKAKKTNAGIRRPEKPPYSYIALIVMA IQSSPTKRLTLSEIYQFLQSRFPFFRGSYQGWKNSVRHNLSLNECFIKLPKGLGRPGKGH YWTIDPASEFMFEEGSFRRRPRGFRRKCQALKPMYSMMNGLGFNHLPDTYGFQGSAGGLS CPPNSLALEGGLGMMNGHLPGNVDGMALPSHSVPHLPSNGGHSYMGGCGGAAAGEYPHHD SSVPASPLLPTGAGGVMEPHAVYSGSAAAWPPSASAALNSGASYIKQQPLSPCNPAANPL SGSLSTHSLEQPYLHQNSHNAPAELQGIPRYHSQSPSMCDRKEFVFSFNAMASSSMHSAG GGSYYHQQVTYQDIKPCVM
Function	Probable transcription activator for a number of lung-specific genes.
Tissue Specificity	Expressed in lung and placenta.
Reactome Pathway	Regulation of CDH11 gene transcription (R-HSA-9762293 ) Formation of lateral plate mesoderm (R-HSA-9758920 )

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Alveolar capillary dysplasia with misalignment of pulmonary veins	DIS6CNDL	Definitive	Autosomal dominant	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[5]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[9]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[10]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[11]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Genetic Variation	[12]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Altered Expression	[4]
Mastocytosis	DIS1TEE0	Strong	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Pneumonia	DIS8EF3M	Strong	Biomarker	[16]
Pneumonitis	DIS88E0K	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[17]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[18]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[16]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[19]
VACTERL/vater association	DISJNE30	Strong	Biomarker	[20]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[8]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[11]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Lung carcinoma	DISTR26C	moderate	Biomarker	[8]
Persistent fetal circulation syndrome	DISSDYEX	moderate	Biomarker	[21]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[11]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[22]
Congenital diaphragmatic hernia	DIS0IPVU	Limited	Biomarker	[23]
Granular corneal dystrophy type II	DISAEE20	Limited	Genetic Variation	[24]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[25]
Hypoplastic left heart syndrome	DISSLFZ4	Limited	Genetic Variation	[26]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[22]
Invasive ductal breast carcinoma	DIS43J58	Limited	Posttranslational Modification	[27]
Type-1 diabetes	DIS7HLUB	Limited	Altered Expression	[28]
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⏷ Show the Full List of 41 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Forkhead box protein F1 (FOXF1).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Forkhead box protein F1 (FOXF1).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein F1 (FOXF1).	[35]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Forkhead box protein F1 (FOXF1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Forkhead box protein F1 (FOXF1).	[38]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Forkhead box protein F1 (FOXF1).	[39]
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⏷ Show the Full List of 6 Drug(s)

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Forkhead box protein F1 (FOXF1).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Forkhead box protein F1 (FOXF1).	[31]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Forkhead box protein F1 (FOXF1).	[33]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Forkhead box protein F1 (FOXF1).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Forkhead box protein F1 (FOXF1).	[36]
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References

1	Cytoplasmic mislocalization of overexpressed FOXF1 is associated with the malignancy and metastasis of colorectal adenocarcinomas.Exp Mol Pathol. 2013 Feb;94(1):262-9. doi: 10.1016/j.yexmp.2012.10.014. Epub 2012 Oct 24.
2	Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
3	Bioinformatic analysis of the prognostic value and potential regulatory network of FOXF1 in papillary thyroid cancer.Biofactors. 2019 Nov;45(6):902-911. doi: 10.1002/biof.1561. Epub 2019 Sep 9.
4	What's the FOX Got to Do with the KITten? Regulating the Lineage-Specific Transcriptional Landscape in GIST.Cancer Discov. 2018 Feb;8(2):146-149. doi: 10.1158/2159-8290.CD-17-1370.
5	Polymorphisms of the FOXF1 and MHC locus genes in individuals undergoing esophageal acid reflux assessments.Dis Esophagus. 2017 Feb 1;30(2):1-7. doi: 10.1111/dote.12456.
6	Gene expression of forkhead transcription factors in the normal and diseased human prostate.BJU Int. 2009 Jun;103(11):1574-80. doi: 10.1111/j.1464-410X.2009.08351.x. Epub 2009 Feb 11.
7	Circular RNA circNASP modulates the malignant behaviors in osteosarcoma via miR-1253/FOXF1 pathway.Biochem Biophys Res Commun. 2018 Jun 2;500(2):511-517. doi: 10.1016/j.bbrc.2018.04.131. Epub 2018 Apr 21.
8	FOXF1 Induces Epithelial-Mesenchymal Transition in Colorectal Cancer Metastasis by Transcriptionally Activating SNAI1.Neoplasia. 2018 Oct;20(10):996-1007. doi: 10.1016/j.neo.2018.08.004. Epub 2018 Sep 10.
9	Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling.BMC Cancer. 2016 Feb 23;16:142. doi: 10.1186/s12885-016-2196-2.
10	Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk.Int J Cancer. 2013 Oct 1;133(7):1751-5. doi: 10.1002/ijc.28160. Epub 2013 Apr 16.
11	Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.Pharmacogenomics J. 2018 Apr;18(2):262-269. doi: 10.1038/tpj.2017.9. Epub 2017 Apr 11.
12	Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma.Cancer Med. 2015 Nov;4(11):1700-4. doi: 10.1002/cam4.500. Epub 2015 Aug 15.
13	Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene.Am J Respir Cell Mol Biol. 2008 Oct;39(4):390-9. doi: 10.1165/rcmb.2008-0044OC. Epub 2008 Apr 17.
14	Differential expression of invasion promoting genes in childhood rhabdomyosarcoma.Int J Oncol. 2011 Apr;38(4):993-1000. doi: 10.3892/ijo.2011.921. Epub 2011 Jan 24.
15	FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor.Cancer Discov. 2018 Feb;8(2):234-251. doi: 10.1158/2159-8290.CD-17-0468. Epub 2017 Nov 21.
16	FOXF1 maintains endothelial barrier function and prevents edema after lung injury.Sci Signal. 2016 Apr 19;9(424):ra40. doi: 10.1126/scisignal.aad1899.
17	Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development.J Med Genet. 2020 May;57(5):296-300. doi: 10.1136/jmedgenet-2019-106095. Epub 2019 Oct 29.
18	FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.Cell Rep. 2018 Apr 10;23(2):442-458. doi: 10.1016/j.celrep.2018.03.067.
19	FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21(Cip1) CDK inhibitor.Oncogene. 2017 Feb 9;36(6):850-862. doi: 10.1038/onc.2016.254. Epub 2016 Jul 18.
20	Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association.Hum Mutat. 2015 Dec;36(12):1150-4. doi: 10.1002/humu.22859. Epub 2015 Sep 14.
21	Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects.Pulm Circ. 2018 Jul-Sep;8(3):2045894018795143. doi: 10.1177/2045894018795143. Epub 2018 Jul 30.
22	Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation.J Med Genet. 2013 Mar;50(3):163-73. doi: 10.1136/jmedgenet-2012-101288. Epub 2013 Jan 18.
23	Downregulation of Forkhead box F1 gene expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia.Pediatr Surg Int. 2016 Dec;32(12):1121-1126. doi: 10.1007/s00383-016-3967-1. Epub 2016 Sep 23.
24	A novel FOXF1 mutation associated with alveolar capillary dysplasia and coexisting colobomas and hemihyperplasia.J Perinatol. 2015 Feb;35(2):155-7. doi: 10.1038/jp.2014.187.
25	Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype.Hum Genet. 2019 Dec;138(11-12):1301-1311. doi: 10.1007/s00439-019-02073-x. Epub 2019 Nov 4.
26	Alveolar capillary dysplasia with misalignment of the pulmonary veins and hypoplastic left heart sequence caused by an in frame deletion within FOXF1.Am J Med Genet A. 2019 Jul;179(7):1325-1329. doi: 10.1002/ajmg.a.61162. Epub 2019 May 9.
27	Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer.Cancer Res. 2010 Jul 15;70(14):6047-58. doi: 10.1158/0008-5472.CAN-10-1576. Epub 2010 Jun 29.
28	Comprehensive evaluation of differential lncRNA and gene expression in patients with intervertebral disc degeneration.Mol Med Rep. 2018 Aug;18(2):1504-1512. doi: 10.3892/mmr.2018.9128. Epub 2018 Jun 5.
29	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
30	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
31	Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
32	Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
33	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
34	Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
35	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
36	Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
37	Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
38	Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
39	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.