Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0GTO1Z)

• DOT Name: Transmembrane protease serine 3 (TMPRSS3)
• Synonyms: EC 3.4.21.-; Serine protease TADG-12; Tumor-associated differentially-expressed gene 12 protein
• Gene Name: TMPRSS3
• Related Disease:
  Nonsyndromic genetic hearing loss
  Advanced cancer
  Auditory neuropathy
  Autosomal recessive nonsyndromic hearing loss 16
  Autosomal recessive nonsyndromic hearing loss 4
  Autosomal recessive nonsyndromic hearing loss 8
  Autosomal recessive nonsyndromic hearing loss 9
  Breast cancer
  Breast carcinoma
  Carcinoma
  Deafness
  Epithelial ovarian cancer
  Glioma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Pneumoconiosis
  Unverricht-Lundborg syndrome
  Autoimmune polyendocrine syndrome type 1
  Movement disorder
  Hearing loss, autosomal recessive
  Gastric cancer
  Nasopharyngeal carcinoma
  Sensorineural hearing loss disorder
  Stomach cancer
• UniProt ID: TMPS3_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF00057 ; PF15494 ; PF00089
• Sequence:
  MGENDPPAVEAPFSFRSLFGLDDLKISPVAPDADAVAAQILSLLPLKFFPIIVIGIIALI
  LALAIGLGIHFDCSGKYRCRSSFKCIELIARCDGVSDCKDGEDEYRCVRVGGQNAVLQVF
  TAASWKTMCSDDWKGHYANVACAQLGFPSYVSSDNLRVSSLEGQFREEFVSIDHLLPDDK
  VTALHHSVYVREGCASGHVVTLQCTACGHRRGYSSRIVGGNMSLLSQWPWQASLQFQGYH
  LCGGSVITPLWIITAAHCVYDLYLPKSWTIQVGLVSLLDNPAPSHLVEKIVYHSKYKPKR
  LGNDIALMKLAGPLTFNEMIQPVCLPNSEENFPDGKVCWTSGWGATEDGAGDASPVLNHA
  AVPLISNKICNHRDVYGGIISPSMLCAGYLTGGVDSCQGDSGGPLVCQERRLWKLVGATS
  FGIGCAEVNKPGVYTRVTSFLDWIHEQMERDLKT
• Function: Probable serine protease that plays a role in hearing. Acts as a permissive factor for cochlear hair cell survival and activation at the onset of hearing and is required for saccular hair cell survival. Activates ENaC (in vitro).
• Tissue Specificity: Expressed in many tissues including fetal cochlea. Isoform T is found at increased levels in some carcinomas.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Auditory neuropathy	DISM6GAU	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 16	DISQXGDY	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 4	DISCJIDF	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 8	DISR7AAN	Strong	Autosomal recessive	[4]
Autosomal recessive nonsyndromic hearing loss 9	DISUKXHK	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Deafness	DISKCLH4	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[8]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[2]
Pneumoconiosis	DISSJLBN	Strong	Biomarker	[11]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Genetic Variation	[12]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	moderate	Genetic Variation	[13]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[14]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[15]
Gastric cancer	DISXGOUK	Limited	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[10]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Posttranslational Modification	[17]
Stomach cancer	DISKIJSX	Limited	Biomarker	[16]

2 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 Transmembrane protease serine 3 (TMPRSS3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane protease serine 3 (TMPRSS3).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane protease serine 3 (TMPRSS3).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transmembrane protease serine 3 (TMPRSS3).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transmembrane protease serine 3 (TMPRSS3).	[22]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[23]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[26]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Transmembrane protease serine 3 (TMPRSS3).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[28]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Transmembrane protease serine 3 (TMPRSS3).	[29]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer.Cancer Res. 2000 May 15;60(10):2602-6.
• [3] Hereditary deafness and phenotyping in humans.Br Med Bull. 2002;63:73-94. doi: 10.1093/bmb/63.1.73.
• [4] Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. J Mol Med (Berl). 2002 Feb;80(2):124-31. doi: 10.1007/s00109-001-0310-6. Epub 2001 Dec 18.
• [5] Dysregulation of TMPRSS3 and TNFRSF11B correlates with tumorigenesis and poor prognosis in patients with breast cancer.Oncol Rep. 2017 Apr;37(4):2057-2062. doi: 10.3892/or.2017.5449. Epub 2017 Feb 14.
• [6] Ovarian tumor cells express a novel multi-domain cell surface serine protease.Biochim Biophys Acta. 2000 Nov 15;1502(3):337-50. doi: 10.1016/s0925-4439(00)00058-2.
• [7] Hereditary hearing loss: a 96 gene targeted sequencing protocol reveals novel alleles in a series of Italian and Qatari patients.Gene. 2014 Jun 1;542(2):209-16. doi: 10.1016/j.gene.2014.03.033. Epub 2014 Mar 20.
• [8] A novel genome-based approach correlates TMPRSS3 overexpression in ovarian cancer with DNA hypomethylation.Gynecol Oncol. 2012 Jun;125(3):720-6. doi: 10.1016/j.ygyno.2012.03.026. Epub 2012 Mar 21.
• [9] Knockdown of TMPRSS3 inhibits cell proliferation, migration/invasion and induces apoptosis of glioma cells.J Cell Biochem. 2019 May;120(5):7794-7801. doi: 10.1002/jcb.28054. Epub 2018 Nov 15.
• [10] Knockdown of TMPRSS3, a Transmembrane Serine Protease, Inhibits Proliferation, Migration, and Invasion in Human Nasopharyngeal Carcinoma Cells.Oncol Res. 2018 Jan 19;26(1):95-101. doi: 10.3727/096504017X14920318811695. Epub 2017 Apr 12.
• [11] Pathway analysis for a genome-wide association study of pneumoconiosis.Toxicol Lett. 2015 Jan 5;232(1):284-92. doi: 10.1016/j.toxlet.2014.10.028. Epub 2014 Nov 4.
• [12] Coexistence of Unverricht-Lundborg disease and congenital deafness: molecular resolution of a complex comorbidity.Epilepsia. 2009 Jun;50(6):1612-5. doi: 10.1111/j.1528-1167.2008.01937.x. Epub 2008 Dec 15.
• [13] Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis.Genomics. 1998 Jan 1;47(1):64-70. doi: 10.1006/geno.1997.5066.
• [14] Putative TMPRSS3/GJB2 digenic inheritance of hearing loss detected by targeted resequencing.Mol Cell Probes. 2017 Jun;33:24-27. doi: 10.1016/j.mcp.2017.03.001. Epub 2017 Mar 3.
• [15] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [16] Knockdown of TMPRSS3 inhibits gastric cancer cell proliferation, invasion and EMT via regulation of the ERK1/2 and PI3K/Akt pathways.Biomed Pharmacother. 2018 Nov;107:841-848. doi: 10.1016/j.biopha.2018.08.023. Epub 2018 Aug 22.
• [17] TMPRSS3 regulates cell viability and apoptosis processes of HEI-OC1 cells via regulation of the circ-Slc4a2, miR-182 and Akt cascade.J Gene Med. 2019 Oct;21(10):e3118. doi: 10.1002/jgm.3118. Epub 2019 Sep 4.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [21] Global gene expression profiles induced by phytoestrogens in human breast cancer cells. Endocr Relat Cancer. 2008 Mar;15(1):161-73.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [24] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [25] 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.
• [26] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.