Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGT2OT)

• DOT Name: Hepatocyte nuclear factor 3-gamma (FOXA3)
• Synonyms: HNF-3-gamma; HNF-3G; Fork head-related protein FKH H3; Forkhead box protein A3; Transcription factor 3G; TCF-3G
• Gene Name: FOXA3
• Related Disease:
  Neoplasm
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Barrett esophagus
  Carcinoma of esophagus
  Esophageal cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm of esophagus
  Non-alcoholic steatohepatitis
  Prostate cancer
  Prostate neoplasm
  Pulmonary disease
  Coronary heart disease
  Non-insulin dependent diabetes
• UniProt ID: FOXA3_HUMAN
• PDB ID: 1VTN
• Pfam ID: PF00250 ; PF08430
• Sequence:
  MLGSVKMEAHDLAEWSYYPEAGEVYSPVTPVPTMAPLNSYMTLNPLSSPYPPGGLPASPL
  PSGPLAPPAPAAPLGPTFPGLGVSGGSSSSGYGAPGPGLVHGKEMPKGYRRPLAHAKPPY
  SYISLITMAIQQAPGKMLTLSEIYQWIMDLFPYYRENQQRWQNSIRHSLSFNDCFVKVAR
  SPDKPGKGSYWALHPSSGNMFENGCYLRRQKRFKLEEKVKKGGSGAATTTRNGTGSAAST
  TTPAATVTSPPQPPPPAPEPEAQGGEDVGALDCGSPASSTPYFTGLELPGELKLDAPYNF
  NHPFSINNLMSEQTPAPPKLDVGFGGYGAEGGEPGVYYQGLYSRSLLNAS
• Function: Transcription factor that is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; binds to and activates transcription from the G6PC1 promoter. Binds to the CYP3A4 promoter and activates its transcription in cooperation with CEBPA. Binds to the CYP3A7 promoter together with members of the CTF/NF-I family. Involved in regulation of neuronal-specific transcription. May be involved in regulation of spermatogenesis.
• Tissue Specificity: Expressed in erythroleukemia and hepatoma cell lines and in liver and pancreas. Not expressed in any other cell lines or tissues examined.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway: Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[2]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[2]
Non-alcoholic steatohepatitis	DIST4788	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[7]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the expression of Hepatocyte nuclear factor 3-gamma (FOXA3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hepatocyte nuclear factor 3-gamma (FOXA3).	[17]

References

• [1] Transcriptomic characterization of hepatocellular carcinoma with CTNNB1 mutation.PLoS One. 2014 May 5;9(5):e95307. doi: 10.1371/journal.pone.0095307. eCollection 2014.
• [2] Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in esophageal cancer.Oncol Lett. 2019 May;17(5):4351-4360. doi: 10.3892/ol.2019.10078. Epub 2019 Feb 26.
• [3] Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis.Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1574-1587. doi: 10.1161/ATVBAHA.119.312610. Epub 2019 Jul 11.
• [4] Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors.Cell Res. 2019 Feb;29(2):124-135. doi: 10.1038/s41422-018-0111-x. Epub 2018 Dec 18.
• [5] Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer.Gene. 2019 Feb 15;685:202-210. doi: 10.1016/j.gene.2018.11.022. Epub 2018 Nov 9.
• [6] The Interaction between Pesticide Use and Genetic Variants Involved in Lipid Metabolism on Prostate Cancer Risk.J Cancer Epidemiol. 2012;2012:358076. doi: 10.1155/2012/358076. Epub 2012 Aug 2.
• [7] SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production.J Clin Invest. 2009 Oct;119(10):2914-24. doi: 10.1172/JCI39731. Epub 2009 Sep 14.
• [8] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [9] Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ER signaling in type 2 diabetes mellitus (T2DM).Biochem Biophys Res Commun. 2017 Aug 26;490(3):786-793. doi: 10.1016/j.bbrc.2017.06.118. Epub 2017 Jun 21.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [17] 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.