Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIK337D)

• DOT Name: Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1)
• Synonyms: Androgen receptor coactivator 55 kDa protein; Androgen receptor-associated protein of 55 kDa; Hydrogen peroxide-inducible clone 5 protein; Hic-5
• Gene Name: TGFB1I1
• Related Disease:
  Arteriosclerosis
  Astrocytoma
  Atherosclerosis
  Breast neoplasm
  Colorectal carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glomerulonephritis
  Hepatocellular carcinoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Prostate neoplasm
  Advanced cancer
  Androgenetic alopecia
  Bone osteosarcoma
  Chronic pancreatitis
  Osteoarthritis
  Osteosarcoma
  Pancreatic cancer
• UniProt ID: TGFI1_HUMAN
• Pfam ID: PF00412 ; PF03535
• Sequence:
  MEDLDALLSDLETTTSHMPRSGAPKERPAEPLTPPPSYGHQPQTGSGESSGASGDKDHLY
  STVCKPRSPKPAAPAAPPFSSSSGVLGTGLCELDRLLQELNATQFNITDEIMSQFPSSKV
  ASGEQKEDQSEDKKRPSLPSSPSPGLPKASATSATLELDRLMASLSDFRVQNHLPASGPT
  QPPVVSSTNEGSPSPPEPTGKGSLDTMLGLLQSDLSRRGVPTQAKGLCGSCNKPIAGQVV
  TALGRAWHPEHFVCGGCSTALGGSSFFEKDGAPFCPECYFERFSPRCGFCNQPIRHKMVT
  ALGTHWHPEHFCCVSCGEPFGDEGFHEREGRPYCRRDFLQLFAPRCQGCQGPILDNYISA
  LSALWHPDCFVCRECFAPFSGGSFFEHEGRPLCENHFHARRGSLCATCGLPVTGRCVSAL
  GRRFHPDHFTCTFCLRPLTKGSFQERAGKPYCQPCFLKLFG
• Function: Functions as a molecular adapter coordinating multiple protein-protein interactions at the focal adhesion complex and in the nucleus. Links various intracellular signaling modules to plasma membrane receptors and regulates the Wnt and TGFB signaling pathways. May also regulate SLC6A3 and SLC6A4 targeting to the plasma membrane hence regulating their activity. In the nucleus, functions as a nuclear receptor coactivator regulating glucocorticoid, androgen, mineralocorticoid and progesterone receptor transcriptional activity. May play a role in the processes of cell growth, proliferation, migration, differentiation and senescence. May have a zinc-dependent DNA-binding activity.
• Tissue Specificity: Expressed in platelets, smooth muscle and prostate stromal cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Glomerulonephritis	DISPZIQ3	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[12]
Androgenetic alopecia	DISSJR1P	Limited	Biomarker	[13]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[14]
Chronic pancreatitis	DISBUOMJ	Limited	Altered Expression	[15]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[16]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[14]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[17]

26 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 Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[24]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[25]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[27]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[29]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[30]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[31]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[32]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[33]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[35]
T83193	DMHO29Y	Patented	T83193 decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[38]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[37]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[39]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[20]

3 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 Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[36]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transforming growth factor beta-1-induced transcript 1 protein (TGFB1I1).	[36]

References

• [1] Role of Hic-5 in the formation of microvilli-like structures and the monocyte-endothelial interaction that accelerates atherosclerosis.Cardiovasc Res. 2015 Mar 1;105(3):361-71. doi: 10.1093/cvr/cvv003. Epub 2015 Jan 12.
• [2] Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.Oncotarget. 2014 Dec 30;5(24):12593-606. doi: 10.18632/oncotarget.2518.
• [3] Hic-5 remodeling of the stromal matrix promotes breast tumor progression.Oncogene. 2017 May 11;36(19):2693-2703. doi: 10.1038/onc.2016.422. Epub 2016 Nov 28.
• [4] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.Oncogene. 2018 Mar;37(9):1205-1219. doi: 10.1038/s41388-017-0033-y. Epub 2017 Dec 15.
• [5] The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis.Endocrinology. 2009 Aug;150(8):3863-70. doi: 10.1210/en.2009-0008. Epub 2009 Apr 23.
• [6] Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGF1-independent manner.Oncotarget. 2017 Jul 31;8(47):82506-82530. doi: 10.18632/oncotarget.19714. eCollection 2017 Oct 10.
• [7] HIC-5 in cancer-associated fibroblasts contributes to esophageal squamous cell carcinoma progression.Cell Death Dis. 2019 Nov 18;10(12):873. doi: 10.1038/s41419-019-2114-z.
• [8] Hydrogen peroxide-inducible clone-5 regulates mesangial cell proliferation in proliferative glomerulonephritis in mice.PLoS One. 2015 Apr 2;10(4):e0122773. doi: 10.1371/journal.pone.0122773. eCollection 2015.
• [9] Hydrogen peroxide inducible clone-5 sustains NADPH oxidase-dependent reactive oxygen species-c-jun N-terminal kinase signaling in hepatocellular carcinoma.Oncogenesis. 2019 Aug 6;8(8):40. doi: 10.1038/s41389-019-0149-8.
• [10] Integrative genomic signatures of hepatocellular carcinoma derived from nonalcoholic Fatty liver disease.PLoS One. 2015 May 20;10(5):e0124544. doi: 10.1371/journal.pone.0124544. eCollection 2015.
• [11] Expression of AR associated protein 55 (ARA55) and androgen receptor in prostate cancer.Prostate. 2003 Sep 1;56(4):280-6. doi: 10.1002/pros.10262.
• [12] A mitochondrial ROS pathway controls matrix metalloproteinase 9 levels and invasive properties in RAS-activated cancer cells.FEBS J. 2019 Feb;286(3):459-478. doi: 10.1111/febs.14671. Epub 2018 Oct 13.
• [13] Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla.J Dermatol Sci. 2011 Jan;61(1):1-6. doi: 10.1016/j.jdermsci.2010.10.015. Epub 2010 Nov 3.
• [14] The adaptor protein ARA55 and the nuclear kinase HIPK1 assist c-Myb in recruiting p300 to chromatin.Biochim Biophys Acta Gene Regul Mech. 2017 Jul;1860(7):751-760. doi: 10.1016/j.bbagrm.2017.05.001. Epub 2017 May 8.
• [15] Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-B (p65)/IL-6 signalling pathway.J Cell Mol Med. 2020 Jan;24(2):1488-1503. doi: 10.1111/jcmm.14833. Epub 2019 Dec 3.
• [16] Alleviation of murine osteoarthritis by deletion of the focal adhesion mechanosensitive adapter, Hic-5.Sci Rep. 2019 Oct 31;9(1):15770. doi: 10.1038/s41598-019-52301-7.
• [17] Hic-5 in pancreatic stellate cells affects proliferation, apoptosis, migration, invasion of pancreatic cancer cells and postoperative survival time of pancreatic cancer.Biomed Pharmacother. 2020 Jan;121:109355. doi: 10.1016/j.biopha.2019.109355. Epub 2019 Nov 1.
• [18] 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.
• [19] 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.
• [20] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [21] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [24] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [25] 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.
• [26] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [27] A pilot study on the transcriptional response of androgen- and insulin-related genes in peripheral blood mononuclear cells induced by testosterone administration in hypogonadal men. J Biol Regul Homeost Agents. 2011 Apr-Jun;25(2):291-4.
• [28] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [29] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [30] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [31] 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.
• [32] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [33] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [34] 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.
• [35] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [36] 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.
• [37] Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res. 2007 Mar 1;616(1-2):60-9. doi: 10.1016/j.mrfmmm.2006.11.022. Epub 2006 Dec 18.
• [38] 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.
• [39] Maternal exposure to dibutyl phthalate (DBP) impairs angiogenesis and AR signalling pathway through suppression of TGFB1I1 in hypospadias offspring. Ecotoxicol Environ Saf. 2024 Jan 15;270:115941. doi: 10.1016/j.ecoenv.2024.115941. Epub 2024 Jan 6.