Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEXJ9SL)

• DOT Name: Forkhead box protein H1 (FOXH1)
• Synonyms: Forkhead activin signal transducer 1; Fast-1; hFAST-1; Forkhead activin signal transducer 2; Fast-2
• Gene Name: FOXH1
• Related Disease:
  Clear cell renal carcinoma
  Colorectal carcinoma
  Friedreich ataxia 1
  Head and neck cancer
  Head and neck carcinoma
  Myeloid leukaemia
  Renal cell carcinoma
  Transposition of the great arteries
  Ventricular septal defect
  Tetralogy of fallot
  Congenital heart malformation
  Holoprosencephaly
• UniProt ID: FOXH1_HUMAN
• PDB ID: 5XOC; 7YZB
• Pfam ID: PF00250
• Sequence:
  MGPCSGSRLGPPEAESPSQPPKRRKKRYLRHDKPPYTYLAMIALVIQAAPSRRLKLAQII
  RQVQAVFPFFREDYEGWKDSIRHNLSSNRCFRKVPKDPAKPQAKGNFWAVDVSLIPAEAL
  RLQNTALCRRWQNGGARGAFAKDLGPYVLHGRPYRPPSPPPPPSEGFSIKSLLGGSGEGA
  PWPGLAPQSSPVPAGTGNSGEEAVPTPPLPSSERPLWPLCPLPGPTRVEGETVQGGAIGP
  STLSPEPRAWPLHLLQGTAVPGGRSSGGHRASLWGQLPTSYLPIYTPNVVMPLAPPPTSC
  PQCPSTSPAYWGVAPETRGPPGLLCDLDALFQGVPPNKSIYDVWVSHPRDLAAPGPGWLL
  SWCSL
• Function: Transcriptional activator. Recognizes and binds to the DNA sequence 5'-TGT[GT][GT]ATT-3'. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling. Forms a transcriptionally active complex containing FOXH1/SMAD2/SMAD4 on a site on the GSC promoter called TARE (TGF-beta/activin response element).
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Signaling by Activin (R-HSA-1502540)
  Germ layer formation at gastrulation (R-HSA-9754189)
  Formation of axial mesoderm (R-HSA-9796292)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Friedreich ataxia 1	DIS285GE	Strong	Biomarker	[3]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[4]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[4]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[1]
Transposition of the great arteries	DISPXJ8X	Strong	Biomarker	[6]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[7]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[8]
Congenital heart malformation	DIS7LR56	Limited	Unknown	[9]
Holoprosencephaly	DISR35EC	Limited	Biomarker	[10]

1 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 H1 (FOXH1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Forkhead box protein H1 (FOXH1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein H1 (FOXH1).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Forkhead box protein H1 (FOXH1).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Forkhead box protein H1 (FOXH1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Forkhead box protein H1 (FOXH1).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Forkhead box protein H1 (FOXH1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Forkhead box protein H1 (FOXH1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Forkhead box protein H1 (FOXH1).	[17]

References

• [1] Smad4 suppresses the progression of renal cell carcinoma via the activation of forkhead box protein H1.Mol Med Rep. 2015 Apr;11(4):2717-22. doi: 10.3892/mmr.2014.3061. Epub 2014 Dec 8.
• [2] FAST1 promotes the migration and invasion of colorectal cancer cells.Biochem Biophys Res Commun. 2019 Feb 5;509(2):407-413. doi: 10.1016/j.bbrc.2018.12.122. Epub 2018 Dec 26.
• [3] FAST-1 antisense RNA epigenetically alters FXN expression.Sci Rep. 2018 Nov 21;8(1):17217. doi: 10.1038/s41598-018-35639-2.
• [4] The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer.Int J Cancer. 2014 Nov 15;135(10):2424-36. doi: 10.1002/ijc.28885. Epub 2014 Apr 19.
• [5] A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1.Cancer Discov. 2019 Jul;9(7):962-979. doi: 10.1158/2159-8290.CD-18-1391. Epub 2019 May 8.
• [6] Mechanism responsible for D-transposition of the great arteries: Is this part of the spectrum of right isomerism?.Congenit Anom (Kyoto). 2016 Sep;56(5):196-202. doi: 10.1111/cga.12176.
• [7] Forkhead box H1 (FOXH1) sequence variants in ventricular septal defect.Int J Cardiol. 2010 Nov 5;145(1):83-5. doi: 10.1016/j.ijcard.2009.05.030. Epub 2009 Jun 13.
• [8] Functionally significant, rare transcription factor variants in tetralogy of Fallot.PLoS One. 2014 Aug 5;9(8):e95453. doi: 10.1371/journal.pone.0095453. eCollection 2014.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway.Hum Mutat. 2016 Dec;37(12):1329-1339. doi: 10.1002/humu.23038. Epub 2016 Aug 23.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.