Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP46PZM)

• DOT Name: Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5)
• Synonyms: ITI heavy chain H5; ITI-HC5; Inter-alpha-inhibitor heavy chain 5
• Gene Name: ITIH5
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Gastric cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Skin disease
  Stomach cancer
  Thyroid tumor
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hirschsprung disease
  Invasive ductal breast carcinoma
  Pancreatic cancer
  Von willebrand disease
• UniProt ID: ITIH5_HUMAN
• Pfam ID: PF06668 ; PF08487 ; PF00092
• Sequence:
  MLLLLGLCLGLSLCVGSQEEAQSWGHSSEQDGLRVPRQVRLLQRLKTKPLMTEFSVKSTI
  ISRYAFTTVSCRMLNRASEDQDIEFQMQIPAAAFITNFTMLIGDKVYQGEITEREKKSGD
  RVKEKRNKTTEENGEKGTEIFRASAVIPSKDKAAFFLSYEELLQRRLGKYEHSISVRPQQ
  LSGRLSVDVNILESAGIASLEVLPLHNSRQRGSGRGEDDSGPPPSTVINQNETFANIIFK
  PTVVQQARIAQNGILGDFIIRYDVNREQSIGDIQVLNGYFVHYFAPKDLPPLPKNVVFVL
  DSSASMVGTKLRQTKDALFTILHDLRPQDRFSIIGFSNRIKVWKDHLISVTPDSIRDGKV
  YIHHMSPTGGTDINGALQRAIRLLNKYVAHSGIGDRSVSLIVFLTDGKPTVGETHTLKIL
  NNTREAARGQVCIFTIGIGNDVDFRLLEKLSLENCGLTRRVHEEEDAGSQLIGFYDEIRT
  PLLSDIRIDYPPSSVVQATKTLFPNYFNGSEIIIAGKLVDRKLDHLHVEVTASNSKKFII
  LKTDVPVRPQKAGKDVTGSPRPGGDGEGDTNHIERLWSYLTTKELLSSWLQSDDEPEKER
  LRQRAQALAVSYRFLTPFTSMKLRGPVPRMDGLEEAHGMSAAMGPEPVVQSVRGAGTQPG
  PLLKKPYQPRIKISKTSVDGDPHFVVDFPLSRLTVCFNIDGQPGDILRLVSDHRDSGVTV
  NGELIGAPAPPNGHKKQRTYLRTITILINKPERSYLEITPSRVILDGGDRLVLPCNQSVV
  VGSWGLEVSVSANANVTVTIQGSIAFVILIHLYKKPAPFQRHHLGFYIANSEGLSSNCHG
  LLGQFLNQDARLTEDPAGPSQNLTHPLLLQVGEGPEAVLTVKGHQVPVVWKQRKIYNGEE
  QIDCWFARNNAAKLIDGEYKDYLAFHPFDTGMTLGQGMSREL
• Function: May act as a tumor suppressor.
• Tissue Specificity: Abundantly expressed in placenta. Less abundant expression in mammary gland and ovary. Expression is barely detectable levels in all other tissues tested.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Posttranslational Modification	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[1]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[1]
Obesity	DIS47Y1K	Strong	Altered Expression	[10]
Skin disease	DISDW8R6	Strong	Altered Expression	[11]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[12]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[3]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[13]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[14]
Pancreatic cancer	DISJC981	Limited	Biomarker	[4]
Von willebrand disease	DIS3TZCH	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inter-alpha-trypsin inhibitor heavy chain H5 (ITIH5).	[24]

References

• [1] Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome.Epigenetics. 2015;10(10):903-12. doi: 10.1080/15592294.2015.1078049. Epub 2015 Aug 7.
• [2] ITIH5 mediates epigenetic reprogramming of breast cancer cells.Mol Cancer. 2017 Feb 23;16(1):44. doi: 10.1186/s12943-017-0610-2.
• [3] Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours.Carcinogenesis. 2014 Mar;35(3):727-36. doi: 10.1093/carcin/bgt375. Epub 2013 Nov 21.
• [4] ITIH5 induces a shift in TGF- superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death.Mol Carcinog. 2018 Feb;57(2):167-181. doi: 10.1002/mc.22742. Epub 2017 Oct 30.
• [5] The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation.Oncogene. 2008 Jan 31;27(6):865-76. doi: 10.1038/sj.onc.1210669. Epub 2007 Jul 23.
• [6] Gene expression analysis combined with functional genomics approach identifies ITIH5 as tumor suppressor gene in cervical carcinogenesis.Mol Carcinog. 2017 Jun;56(6):1578-1589. doi: 10.1002/mc.22613. Epub 2017 Mar 6.
• [7] Epigenetic inactivation of the novel candidate tumor suppressor gene ITIH5 in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype.Epigenetics. 2014 Sep;9(9):1290-301. doi: 10.4161/epi.32089. Epub 2014 Aug 4.
• [8] Decreased ITIH5 expression is associated with poor prognosis in primary gastric cancer.Med Oncol. 2014 Jul;31(7):53. doi: 10.1007/s12032-014-0053-1. Epub 2014 Jun 10.
• [9] Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer.Clin Exp Metastasis. 2017 Apr;34(3-4):229-239. doi: 10.1007/s10585-017-9840-3. Epub 2017 Mar 13.
• [10] ITIH-5 expression in human adipose tissue is increased in obesity.Obesity (Silver Spring). 2012 Apr;20(4):708-14. doi: 10.1038/oby.2011.268. Epub 2011 Aug 18.
• [11] Inter--trypsin inhibitor heavy chain 5 (ITIH5) is overexpressed in inflammatory skin diseases and affects epidermal morphology in constitutive knockout mice and murine 3D skin models.Exp Dermatol. 2015 Sep;24(9):663-8. doi: 10.1111/exd.12704. Epub 2015 Apr 17.
• [12] Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas.Br J Cancer. 2009 Nov 17;101(10):1782-91. doi: 10.1038/sj.bjc.6605340. Epub 2009 Oct 6.
• [13] Aberrant expression of LncRNA-MIR31HG regulates cell migration and proliferation by affecting miR-31 and miR-31* in Hirschsprung's disease.J Cell Biochem. 2018 Nov;119(10):8195-8203. doi: 10.1002/jcb.26830. Epub 2018 Apr 6.
• [14] ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer.Cancer Lett. 2004 Feb 10;204(1):69-77. doi: 10.1016/j.canlet.2003.09.011.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.