Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80PRHS)

• DOT Name: Forkhead box protein D1 (FOXD1)
• Synonyms: Forkhead-related protein FKHL8; Forkhead-related transcription factor 4; FREAC-4
• Gene Name: FOXD1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Diphtheria
  Glomerulonephritis
  Hereditary chronic pancreatitis
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Renal fibrosis
  Pancreatic cancer
  Melanoma
  Adult glioblastoma
  Bone osteosarcoma
  Glioblastoma multiforme
  Glioma
  Osteoarthritis
  Osteosarcoma
• UniProt ID: FOXD1_HUMAN
• Pfam ID: PF00250
• Sequence:
  MTLSTEMSDASGLAEETDIDVVGEGEDEEDEEEEDDDEGGGGGPRLAVPAQRRRRRRSYA
  GEDELEDLEEEEDDDDILLAPPAGGSPAPPGPAPAAGAGAGGGGGGGGAGGGGSAGSGAK
  NPLVKPPYSYIALITMAILQSPKKRLTLSEICEFISGRFPYYREKFPAWQNSIRHNLSLN
  DCFVKIPREPGNPGKGNYWTLDPESADMFDNGSFLRRRKRFKRQPLLPPNAAAAESLLLR
  GAGAAGGAGDPAAAAALFPPAPPPPPHAYGYGPYGCGYGLQLPPYAPPSALFAAAAAAAA
  AAAFHPHSPPPPPPPHGAAAELARTAFGYRPHPLGAALPGPLPASAAKAGGPGASALARS
  PFSIESIIGGSLGPAAAAAAAAQAAAAAQASPSPSPVAAPPAPGSSGGGCAAQAAVGPAA
  ALTRSLVAAAAAAASSVSSSAALGTLHQGTALSSVENFTARISNC
• Function: Transcription factor involved in regulation of gene expression in a variety of processes, including formation of positional identity in the developing retina, regionalization of the optic chiasm, morphogenesis of the kidney, and neuralization of ectodermal cells. Involved in transcriptional activation of PGF and C3 genes.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Diphtheria	DISZWM55	Strong	Biomarker	[6]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[7]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Genetic Variation	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Pneumonia	DIS8EF3M	Strong	Genetic Variation	[6]
Pneumonitis	DIS88E0K	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[13]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[14]
Pancreatic cancer	DISJC981	moderate	Biomarker	[15]
Melanoma	DIS1RRCY	Disputed	Altered Expression	[16]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[17]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[17]
Glioma	DIS5RPEH	Limited	Genetic Variation	[1]
Osteoarthritis	DIS05URM	Limited	Biomarker	[19]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Forkhead box protein D1 (FOXD1) affects the response to substance of Topotecan.	[35]

3 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 D1 (FOXD1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Forkhead box protein D1 (FOXD1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein D1 (FOXD1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein D1 (FOXD1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Forkhead box protein D1 (FOXD1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Forkhead box protein D1 (FOXD1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein D1 (FOXD1).	[25]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Forkhead box protein D1 (FOXD1).	[26]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Forkhead box protein D1 (FOXD1).	[27]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Forkhead box protein D1 (FOXD1).	[28]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Forkhead box protein D1 (FOXD1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein D1 (FOXD1).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Forkhead box protein D1 (FOXD1).	[31]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Forkhead box protein D1 (FOXD1).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Forkhead box protein D1 (FOXD1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Forkhead box protein D1 (FOXD1).	[33]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Forkhead box protein D1 (FOXD1).	[34]

References

• [1] LncRNA FOXD1-AS1 acts as a potential oncogenic biomarker in glioma.CNS Neurosci Ther. 2020 Jan;26(1):66-75. doi: 10.1111/cns.13152. Epub 2019 May 17.
• [2] Forkhead box D1 promotes proliferation and suppresses apoptosis via regulating polo-like kinase 2 in colorectal cancer.Biomed Pharmacother. 2018 Jul;103:1369-1375. doi: 10.1016/j.biopha.2018.04.190. Epub 2018 May 7.
• [3] SP1-mediated long noncoding RNA POU3F3 accelerates the cervical cancer through miR-127-5p/FOXD1.Biomed Pharmacother. 2019 Sep;117:109133. doi: 10.1016/j.biopha.2019.109133. Epub 2019 Jun 25.
• [4] Deregulated FOX genes in Hodgkin lymphoma.Genes Chromosomes Cancer. 2014 Nov;53(11):917-33. doi: 10.1002/gcc.22204. Epub 2014 Jul 17.
• [5] CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-B pathway in colorectal cancer.Cell Death Dis. 2019 Feb 21;10(3):178. doi: 10.1038/s41419-019-1431-6.
• [6] Ablation of Pericyte-Like Cells in Lungs by Oropharyngeal Aspiration of Diphtheria Toxin.Am J Respir Cell Mol Biol. 2017 Feb;56(2):160-167. doi: 10.1165/rcmb.2016-0083MA.
• [7] Inactivation of MAP3K7 in FOXD1-expressing cells results in loss of mesangial PDGFR and juvenile kidney scarring.Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F336-F344. doi: 10.1152/ajprenal.00493.2017. Epub 2018 Apr 18.
• [8] A novel mouse model of hemangiopericytoma due to loss of Tsc2.Hum Mol Genet. 2018 Dec 15;27(24):4169-4175. doi: 10.1093/hmg/ddy289.
• [9] FOXD1 and Gal-3 Form a Positive Regulatory Loop to Regulate Lung Cancer Aggressiveness.Cancers (Basel). 2019 Nov 28;11(12):1897. doi: 10.3390/cancers11121897.
• [10] MicroRNA-338-5p plays a tumor suppressor role in glioma through inhibition of the MAPK-signaling pathway by binding to FOXD1.J Cancer Res Clin Oncol. 2018 Dec;144(12):2351-2366. doi: 10.1007/s00432-018-2745-y. Epub 2018 Sep 17.
• [11] FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC.Cell Physiol Biochem. 2018;51(6):2716-2731. doi: 10.1159/000495962. Epub 2018 Dec 12.
• [12] 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.
• [13] Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation.J Clin Invest. 2019 Feb 28;129(5):1984-1999. doi: 10.1172/JCI122106. Print 2019 May 1.
• [14] Autophagy in FOXD1 stroma-derived cells regulates renal fibrosis through TGF- and NLRP3 inflammasome pathway.Biochem Biophys Res Commun. 2019 Jan 15;508(3):965-972. doi: 10.1016/j.bbrc.2018.11.090. Epub 2018 Dec 10.
• [15] Down-regulation of miR-30a-5p is Associated with Poor Prognosis and Promotes Chemoresistance of Gemcitabine in Pancreatic Ductal Adenocarcinoma.J Cancer. 2019 Aug 28;10(21):5031-5040. doi: 10.7150/jca.31191. eCollection 2019.
• [16] Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation.Int J Cancer. 2018 Dec 1;143(11):2962-2972. doi: 10.1002/ijc.31799. Epub 2018 Sep 29.
• [17] Silencing of Forkhead box D1 inhibits proliferation and migration in glioma cells.Oncol Rep. 2017 Feb;37(2):1196-1202. doi: 10.3892/or.2017.5344. Epub 2017 Jan 2.
• [18] MiR-30a-5p inhibits osteosarcoma cell proliferation and migration by targeting FOXD1.Biochem Biophys Res Commun. 2018 Sep 5;503(2):1092-1097. doi: 10.1016/j.bbrc.2018.06.121. Epub 2018 Aug 2.
• [19] Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis.PLoS Biol. 2019 Apr 1;17(4):e3000201. doi: 10.1371/journal.pbio.3000201. eCollection 2019 Apr.
• [20] 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.
• [21] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [26] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [27] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [28] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [29] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [32] 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.
• [33] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [35] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.