Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA1T9KK)

• DOT Name: Thrombospondin-4 (THBS4)
• Gene Name: THBS4
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Cardiomyopathy
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Duchenne muscular dystrophy
  Gastric cancer
  High blood pressure
  Liver cirrhosis
  Neuralgia
  Osteoarthritis
  Stomach cancer
  Tendinopathy
  Breast cancer
  Breast carcinoma
  Carcinoma
  Non-insulin dependent diabetes
  Peripheral arterial disease
  Peripheral vascular disease
  Prediabetes syndrome
  Type-1/2 diabetes
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Adenoma
  Hepatocellular carcinoma
  Knee osteoarthritis
  Neoplasm
  Primary cutaneous T-cell lymphoma
• UniProt ID: TSP4_HUMAN
• Pfam ID: PF11598 ; PF00008 ; PF02412 ; PF05735
• Sequence:
  MLAPRGAAVLLLHLVLQRWLAAGAQATPQVFDLLPSSSQRLNPGALLPVLTDPALNDLYV
  ISTFKLQTKSSATIFGLYSSTDNSKYFEFTVMGRLNKAILRYLKNDGKVHLVVFNNLQLA
  DGRRHRILLRLSNLQRGAGSLELYLDCIQVDSVHNLPRAFAGPSQKPETIELRTFQRKPQ
  DFLEELKLVVRGSLFQVASLQDCFLQQSEPLAATGTGDFNRQFLGQMTQLNQLLGEVKDL
  LRQQVKETSFLRNTIAECQACGPLKFQSPTPSTVVPPAPPAPPTRPPRRCDSNPCFRGVQ
  CTDSRDGFQCGPCPEGYTGNGITCIDVDECKYHPCYPGVHCINLSPGFRCDACPVGFTGP
  MVQGVGISFAKSNKQVCTDIDECRNGACVPNSICVNTLGSYRCGPCKPGYTGDQIRGCKA
  ERNCRNPELNPCSVNAQCIEERQGDVTCVCGVGWAGDGYICGKDVDIDSYPDEELPCSAR
  NCKKDNCKYVPNSGQEDADRDGIGDACDEDADGDGILNEQDNCVLIHNVDQRNSDKDIFG
  DACDNCLSVLNNDQKDTDGDGRGDACDDDMDGDGIKNILDNCPKFPNRDQRDKDGDGVGD
  ACDSCPDVSNPNQSDVDNDLVGDSCDTNQDSDGDGHQDSTDNCPTVINSAQLDTDKDGIG
  DECDDDDDNDGIPDLVPPGPDNCRLVPNPAQEDSNSDGVGDICESDFDQDQVIDRIDVCP
  ENAEVTLTDFRAYQTVVLDPEGDAQIDPNWVVLNQGMEIVQTMNSDPGLAVGYTAFNGVD
  FEGTFHVNTQTDDDYAGFIFGYQDSSSFYVVMWKQTEQTYWQATPFRAVAEPGIQLKAVK
  SKTGPGEHLRNSLWHTGDTSDQVRLLWKDSRNVGWKDKVSYRWFLQHRPQVGYIRVRFYE
  GSELVADSGVTIDTTMRGGRLGVFCFSQENIIWSNLKYRCNDTIPEDFQEFQTQNFDRFD
  N
• Function: Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions and is involved in various processes including cellular proliferation, migration, adhesion and attachment, inflammatory response to CNS injury, regulation of vascular inflammation and adaptive responses of the heart to pressure overload and in myocardial function and remodeling. Binds to structural extracellular matrix (ECM) proteins and modulates the ECM in response to tissue damage, contributing to cardioprotective and adaptive ECM remodeling. Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors and protects myocardium from pressure overload. May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury. May play a role in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury in a NOTCH1-dependent manner.
• KEGG Pathway:
  Phagosome (hsa04145)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Malaria (hsa05144)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway: Signaling by PDGF (R-HSA-186797)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[1]
Neuralgia	DISWO58J	Strong	Biomarker	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[9]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Tendinopathy	DISJH7UX	Strong	Altered Expression	[10]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[11]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[11]
Carcinoma	DISH9F1N	moderate	Altered Expression	[12]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Altered Expression	[13]
Peripheral arterial disease	DIS78WFB	moderate	Biomarker	[13]
Peripheral vascular disease	DISXSU1Y	moderate	Biomarker	[13]
Prediabetes syndrome	DISH2I53	moderate	Altered Expression	[13]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[13]
Prostate cancer	DISF190Y	Disputed	Altered Expression	[14]
Prostate carcinoma	DISMJPLE	Disputed	Altered Expression	[14]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[15]
Adenoma	DIS78ZEV	Limited	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]
Knee osteoarthritis	DISLSNBJ	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Posttranslational Modification	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Thrombospondin-4 (THBS4).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Thrombospondin-4 (THBS4).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Thrombospondin-4 (THBS4).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Thrombospondin-4 (THBS4).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Thrombospondin-4 (THBS4).	[22]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Thrombospondin-4 (THBS4).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thrombospondin-4 (THBS4).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Thrombospondin-4 (THBS4).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Thrombospondin-4 (THBS4).	[24]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Thrombospondin-4 (THBS4).	[25]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Thrombospondin-4 (THBS4).	[26]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Thrombospondin-4 (THBS4).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Thrombospondin-4 (THBS4).	[30]

2 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 Thrombospondin-4 (THBS4).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Thrombospondin-4 (THBS4).	[29]

References

• [1] Thrombospondin-4 expression as a prognostic marker in hepatocellular carcinoma.Gene. 2019 May 15;696:219-224. doi: 10.1016/j.gene.2019.02.049. Epub 2019 Feb 22.
• [2] Proteomic analysis of plasma from children with sickle cell anemia and silent cerebral infarction.Haematologica. 2018 Jul;103(7):1136-1142. doi: 10.3324/haematol.2018.187815. Epub 2018 Mar 15.
• [3] Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy.Mol Cell Biol. 2018 Jun 28;38(14):e00114-18. doi: 10.1128/MCB.00114-18. Print 2018 Jul 15.
• [4] Thrombospondin-4 polymorphism (A387P) predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and C-reactive protein levels.Thromb Haemost. 2011 Dec;106(6):1170-8. doi: 10.1160/TH11-03-0206. Epub 2011 Oct 20.
• [5] HPV16(+) -miRNAs in cervical cancer and the anti-tumor role played by miR-5701.J Gene Med. 2019 Nov;21(11):e3126. doi: 10.1002/jgm.3126. Epub 2019 Oct 25.
• [6] THBS4 predicts poor outcomes and promotes proliferation and metastasis in gastric cancer.J Physiol Biochem. 2019 Feb;75(1):117-123. doi: 10.1007/s13105-019-00665-9. Epub 2019 Feb 12.
• [7] Thrombospondin-4 mediates cardiovascular remodelling in angiotensin II-induced hypertension.Cardiovasc Pathol. 2018 Jul-Aug;35:12-19. doi: 10.1016/j.carpath.2018.03.003. Epub 2018 Apr 7.
• [8] Direct, gabapentin-insensitive interaction of a soluble form of the calcium channel subunit (2)-1 with thrombospondin-4.Sci Rep. 2019 Nov 7;9(1):16272. doi: 10.1038/s41598-019-52655-y.
• [9] The Expression of Thrombospondin-4 Correlates with Disease Severity in Osteoarthritic Knee Cartilage.Int J Mol Sci. 2019 Jan 21;20(2):447. doi: 10.3390/ijms20020447.
• [10] MicroRNA 148a-3p promotes Thrombospondin-4 expression and enhances angiogenesis during tendinopathy development by inhibiting Krppel-like factor 6.Biochem Biophys Res Commun. 2018 Jul 12;502(2):276-282. doi: 10.1016/j.bbrc.2018.05.167. Epub 2018 May 26.
• [11] Bisphenol S induced epigenetic and transcriptional changes in human breast cancer cell line MCF-7.Environ Pollut. 2019 Mar;246:697-703. doi: 10.1016/j.envpol.2018.12.084. Epub 2018 Dec 31.
• [12] The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer.PLoS One. 2019 Nov 8;14(11):e0224727. doi: 10.1371/journal.pone.0224727. eCollection 2019.
• [13] Thrombospondin-4 increases with the severity of peripheral arterial disease and is associated with diabetes.Heart Vessels. 2020 Jan;35(1):52-58. doi: 10.1007/s00380-019-01453-7. Epub 2019 Jun 21.
• [14] Reciprocal regulation of long noncoding RNAs THBS4?03 and THBS4 control migration and invasion in prostate cancer cell lines.Mol Med Rep. 2016 Aug;14(2):1451-8. doi: 10.3892/mmr.2016.5443. Epub 2016 Jun 23.
• [15] THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling.Mod Pathol. 2011 Oct;24(10):1390-403. doi: 10.1038/modpathol.2011.99. Epub 2011 Jun 24.
• [16] Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation.BMC Cancer. 2010 Sep 16;10:494. doi: 10.1186/1471-2407-10-494.
• [17] Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.J Clin Oncol. 2005 Jun 10;23(17):3886-96. doi: 10.1200/JCO.2005.11.353. Epub 2005 May 16.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] 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.
• [25] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [26] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [27] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [28] 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.
• [29] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [30] 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.