Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7XPPEL)

• DOT Name: Zinc finger transcription factor Trps1 (TRPS1)
• Synonyms: Tricho-rhino-phalangeal syndrome type I protein; Zinc finger protein GC79
• Gene Name: TRPS1
• Related Disease:
  Breast carcinoma
  Cutaneous squamous cell carcinoma
  Trichorhinophalangeal syndrome type I
  Alopecia
  Benign prostatic hyperplasia
  Bone development disease
  Bone disease
  Bone osteosarcoma
  Brachydactyly
  Breast cancer
  Breast neoplasm
  Carcinoma
  Charlevoix-Saguenay spastic ataxia
  Colon cancer
  Colon carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Exostosis
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Neoplasm
  Obesity
  Osteoporosis
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
  Trichohepatoenteric syndrome
  Trichorhinophalangeal syndrome type II
  Trichorhinophalangeal syndrome, type III
  Adenovirus infection
  Advanced cancer
  Chronic renal failure
  Osteochondrodysplasia
  Skeletal dysplasia
  Trichorhinophalangeal syndrome
  Obsolete trichorhinophalangeal syndrome type I or III
  Refractory multiple myeloma
  Undifferentiated carcinoma
  Acute myelogenous leukaemia
  Basal cell carcinoma
  Basal cell neoplasm
  Ductal breast carcinoma in situ
  Hypertrichosis
• UniProt ID: TRPS1_HUMAN
• Pfam ID: PF00320
• Sequence:
  MVRKKNPPLRNVASEGEGQILEPIGTESKVSGKNKEFSADQMSENTDQSDAAELNHKEEH
  SLHVQDPSSSSKKDLKSAVLSEKAGFNYESPSKGGNFPSFPHDEVTDRNMLAFSSPAAGG
  VCEPLKSPQRAEADDPQDMACTPSGDSLETKEDQKMSPKATEETGQAQSGQANCQGLSPV
  SVASKNPQVPSDGGVRLNKSKTDLLVNDNPDPAPLSPELQDFKCNICGYGYYGNDPTDLI
  KHFRKYHLGLHNRTRQDAELDSKILALHNMVQFSHSKDFQKVNRSVFSGVLQDINSSRPV
  LLNGTYDVQVTSGGTFIGIGRKTPDCQGNTKYFRCKFCNFTYMGNSSTELEQHFLQTHPN
  KIKASLPSSEVAKPSEKNSNKSIPALQSSDSGDLGKWQDKITVKAGDDTPVGYSVPIKPL
  DSSRQNGTEATSYYWCKFCSFSCESSSSLKLLEHYGKQHGAVQSGGLNPELNDKLSRGSV
  INQNDLAKSSEGETMTKTDKSSSGAKKKDFSSKGAEDNMVTSYNCQFCDFRYSKSHGPDV
  IVVGPLLRHYQQLHNIHKCTIKHCPFCPRGLCSPEKHLGEITYPFACRKSNCSHCALLLL
  HLSPGAAGSSRVKHQCHQCSFTTPDVDVLLFHYESVHESQASDVKQEANHLQGSDGQQSV
  KESKEHSCTKCDFITQVEEEISRHYRRAHSCYKCRQCSFTAADTQSLLEHFNTVHCQEQD
  ITTANGEEDGHAISTIKEEPKIDFRVYNLLTPDSKMGEPVSESVVKREKLEEKDGLKEKV
  WTESSSDDLRNVTWRGADILRGSPSYTQASLGLLTPVSGTQEQTKTLRDSPNVEAAHLAR
  PIYGLAVETKGFLQGAPAGGEKSGALPQQYPASGENKSKDESQSLLRRRRGSGVFCANCL
  TTKTSLWRKNANGGYVCNACGLYQKLHSTPRPLNIIKQNNGEQIIRRRTRKRLNPEALQA
  EQLNKQQRGSNEEQVNGSPLERRSEDHLTESHQREIPLPSLSKYEAQGSLTKSHSAQQPV
  LVSQTLDIHKRMQPLHIQIKSPQESTGDPGNSSSVSEGKGSSERGSPIEKYMRPAKHPNY
  SPPGSPIEKYQYPLFGLPFVHNDFQSEADWLRFWSKYKLSVPGNPHYLSHVPGLPNPCQN
  YVPYPTFNLPPHFSAVGSDNDIPLDLAIKHSRPGPTANGASKEKTKAPPNVKNEGPLNVV
  KTEKVDRSTQDELSTKCVHCGIVFLDEVMYALHMSCHGDSGPFQCSICQHLCTDKYDFTT
  HIQRGLHRNNAQVEKNGKPKE
• Function: Transcriptional repressor. Binds specifically to GATA sequences and represses expression of GATA-regulated genes at selected sites and stages in vertebrate development. Regulates chondrocyte proliferation and differentiation. Executes multiple functions in proliferating chondrocytes, expanding the region of distal chondrocytes, activating proliferation in columnar cells and supporting the differentiation of columnar into hypertrophic chondrocytes.
• Tissue Specificity: Ubiquitously expressed in the adult. Found in fetal brain, lung, kidney, liver, spleen and thymus. More highly expressed in androgen-dependent than in androgen-independent prostate cancer cells.

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Cutaneous squamous cell carcinoma	DIS3LXUG	Definitive	Genetic Variation	[2]
Trichorhinophalangeal syndrome type I	DIS2221W	Definitive	Autosomal dominant	[3]
Alopecia	DIS37HU4	Strong	Genetic Variation	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Bone development disease	DISVKAZS	Strong	Biomarker	[6]
Bone disease	DISE1F82	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Carcinoma	DISH9F1N	Strong	Altered Expression	[11]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Genetic Variation	[12]
Colon cancer	DISVC52G	Strong	Biomarker	[13]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[14]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[14]
Exostosis	DIS3VKEI	Strong	Genetic Variation	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Altered Expression	[17]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[19]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[22]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[23]
Trichorhinophalangeal syndrome type II	DISW4YZ1	Strong	Genetic Variation	[24]
Trichorhinophalangeal syndrome, type III	DISS94K4	Strong	Autosomal dominant	[25]
Adenovirus infection	DISUYSBZ	moderate	Biomarker	[26]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[27]
Chronic renal failure	DISGG7K6	moderate	Genetic Variation	[28]
Osteochondrodysplasia	DIS9SPWW	moderate	Genetic Variation	[29]
Skeletal dysplasia	DIS5Z8U6	moderate	Genetic Variation	[29]
Trichorhinophalangeal syndrome	DISO1AEK	moderate	Altered Expression	[30]
Obsolete trichorhinophalangeal syndrome type I or III	DIS74JVT	Supportive	Autosomal dominant	[31]
Refractory multiple myeloma	DIS606GH	Disputed	Genetic Variation	[32]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[33]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[34]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[35]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[35]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Altered Expression	[20]
Hypertrichosis	DISZUK5W	Limited	Biomarker	[36]

14 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 Zinc finger transcription factor Trps1 (TRPS1).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[38]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[39]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[39]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[40]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[41]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[46]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[47]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[49]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[50]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Zinc finger transcription factor Trps1 (TRPS1).	[6]

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 Zinc finger transcription factor Trps1 (TRPS1).	[42]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Zinc finger transcription factor Trps1 (TRPS1).	[43]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Zinc finger transcription factor Trps1 (TRPS1).	[48]

References

• [1] TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.Transl Oncol. 2018 Apr;11(2):416-425. doi: 10.1016/j.tranon.2018.01.009. Epub 2018 Feb 20.
• [2] Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.Nat Commun. 2016 Jul 18;7:12048. doi: 10.1038/ncomms12048.
• [3] Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat Genet. 2000 Jan;24(1):71-4. doi: 10.1038/71717.
• [4] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [5] Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer.Br J Cancer. 2004 Mar 8;90(5):1041-6. doi: 10.1038/sj.bjc.6601648.
• [6] Identification of the GATA factor TRPS1 as a repressor of the osteocalcin promoter. J Biol Chem. 2009 Nov 13;284(46):31690-703. doi: 10.1074/jbc.M109.052316. Epub 2009 Sep 15.
• [7] Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes.Mol Cell Biol. 2002 Dec;22(24):8592-600. doi: 10.1128/MCB.22.24.8592-8600.2002.
• [8] Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression.FEBS Lett. 2014 Mar 3;588(5):801-10. doi: 10.1016/j.febslet.2014.01.041. Epub 2014 Jan 31.
• [9] Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain.Bone. 2019 Jun;123:153-158. doi: 10.1016/j.bone.2019.03.028. Epub 2019 Mar 23.
• [10] TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers.Oncogene. 2018 Sep;37(39):5281-5291. doi: 10.1038/s41388-018-0312-2. Epub 2018 Jun 12.
• [11] Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth.Breast Cancer Res. 2018 Aug 2;20(1):83. doi: 10.1186/s13058-018-1018-7.
• [12] Syndrome disintegration: Exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events.Am J Med Genet A. 2016 Jul;170(7):1820-5. doi: 10.1002/ajmg.a.37684. Epub 2016 May 2.
• [13] Increased expression of TRPS1 affects tumor progression and correlates with patients' prognosis of colon cancer.Biomed Res Int. 2013;2013:454085. doi: 10.1155/2013/454085. Epub 2013 May 26.
• [14] TRIB1 and TRPS1 variants, GG and GE interactions on serum lipid levels, the risk of coronary heart disease and ischemic stroke.Sci Rep. 2019 Feb 20;9(1):2376. doi: 10.1038/s41598-019-38765-7.
• [15] Thricho-rhino-phalangeal syndrome and severe osteoporosis: a rare association or a feature? An effective therapeutic approach with biphosphonates.Am J Med Genet A. 2014 Mar;164A(3):760-3. doi: 10.1002/ajmg.a.36327. Epub 2013 Dec 19.
• [16] Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes.Clin Endocrinol (Oxf). 2018 Mar;88(3):425-431. doi: 10.1111/cen.13535. Epub 2018 Jan 10.
• [17] Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression.Cancer Med. 2018 May;7(5):1921-1932. doi: 10.1002/cam4.1421. Epub 2018 Mar 30.
• [18] TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer.Cell Rep. 2018 Oct 30;25(5):1255-1267.e5. doi: 10.1016/j.celrep.2018.10.023.
• [19] Identification of Novel Potentially Pleiotropic Variants Associated With Osteoporosis and Obesity Using the cFDR Method.J Clin Endocrinol Metab. 2018 Jan 1;103(1):125-138. doi: 10.1210/jc.2017-01531.
• [20] Quantitative immunohistochemical analysis and prognostic significance of TRPS-1, a new GATA transcription factor family member, in breast cancer.Horm Cancer. 2010 Feb;1(1):21-33. doi: 10.1007/s12672-010-0008-8. Epub 2010 Feb 13.
• [21] Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells.Biochim Biophys Acta. 2007 May;1774(5):575-82. doi: 10.1016/j.bbapap.2007.03.011. Epub 2007 Mar 24.
• [22] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [23] Non-ossifying fibroma with a pathologic fracture in a 12-year-old girl with tricho-rhino-phalangeal syndrome: a case report.BMC Med Genet. 2018 Dec 12;19(1):211. doi: 10.1186/s12881-018-0732-4.
• [24] Cornelia de Lange syndrome caused by heterozygous deletions of chromosome 8q24: comments on the article by Pereza et al. [2012].Am J Med Genet A. 2015 Jun;167(6):1426-7. doi: 10.1002/ajmg.a.36974. Epub 2015 Apr 21.
• [25] Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet. 2001 Jan;68(1):81-91. doi: 10.1086/316926. Epub 2000 Dec 7.
• [26] Trps1 regulates biliary epithelial-mesenchymal transition and has roles during biliary fibrosis in liver grafts: a preliminary study.PLoS One. 2015 Apr 17;10(4):e0123233. doi: 10.1371/journal.pone.0123233. eCollection 2015.
• [27] Atypical GATA transcription factor TRPS1 represses gene expression by recruiting CHD4/NuRD(MTA2) and suppresses cell migration and invasion by repressing TP63 expression.Oncogenesis. 2018 Dec 19;7(12):96. doi: 10.1038/s41389-018-0108-9.
• [28] Tricho-rhino-phalangeal syndrome in a 13-year-old girl with chronic renal failure and severe growth retardation.Ren Fail. 2014 May;36(4):619-22. doi: 10.3109/0886022X.2014.882237. Epub 2014 Feb 6.
• [29] Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome.Hum Mol Genet. 2008 Jul 15;17(14):2244-54. doi: 10.1093/hmg/ddn125. Epub 2008 Apr 17.
• [30] Trps1 transcription factor regulates mineralization of dental tissues and proliferation of tooth organ cells.Mol Genet Metab. 2019 Apr;126(4):504-512. doi: 10.1016/j.ymgme.2019.01.014. Epub 2019 Jan 23.
• [31] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [32] Genes and chromosomal breakpoints in the Langer-Giedion syndrome region on human chromosome 8.Hum Genet. 1999 Dec;105(6):619-28. doi: 10.1007/s004399900176.
• [33] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [34] Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia.Blood. 2007 May 1;109(9):4023-7. doi: 10.1182/blood-2006-01-031781. Epub 2007 Jan 23.
• [35] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [36] Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis.PLoS Genet. 2012;8(11):e1003002. doi: 10.1371/journal.pgen.1003002. Epub 2012 Nov 1.
• [37] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [38] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [39] 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.
• [40] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [41] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [42] 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.
• [43] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [44] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [45] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [46] 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.
• [47] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [48] 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.
• [49] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [50] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [51] Identification of the GATA factor TRPS1 as a repressor of the osteocalcin promoter. J Biol Chem. 2009 Nov 13;284(46):31690-703. doi: 10.1074/jbc.M109.052316. Epub 2009 Sep 15.