Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT69BER9)

DOT Name	CCN family member 4 (CCN4)
Synonyms	WNT1-inducible-signaling pathway protein 1; WISP-1; Wnt-1-induced secreted protein
Gene Name	CCN4
Related Disease	Esophageal squamous cell carcinoma ( ) Rheumatoid arthritis ( ) Autoimmune disease ( ) Autoimmune disease, susceptibility to, 6 ( ) Bone osteosarcoma ( ) Breast neoplasm ( ) Carcinoma of esophagus ( ) Colon cancer ( ) Colon carcinoma ( ) Esophageal cancer ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Hypothyroidism ( ) Laryngeal carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Neoplasm of esophagus ( ) Non-alcoholic fatty liver disease ( ) Non-insulin dependent diabetes ( ) Non-small-cell lung cancer ( ) Obesity ( ) Osteoarthritis ( ) Osteosarcoma ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary fibrosis ( ) Squamous cell carcinoma ( ) STAT3-related early-onset multisystem autoimmune disease ( ) Breast cancer ( ) Breast carcinoma ( ) Clear cell renal carcinoma ( ) Renal cell carcinoma ( ) Acute myelogenous leukaemia ( ) Adenocarcinoma ( ) Adult glioblastoma ( ) Advanced cancer ( ) Carcinoma ( ) Desmoid tumour ( ) Gastric cancer ( ) Glioblastoma multiforme ( ) Melanoma ( ) Metastatic malignant neoplasm ( ) Renal fibrosis ( ) Stomach cancer ( ) Type-1/2 diabetes ( )
UniProt ID	CCN4_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00007 ; PF00219 ; PF19035 ; PF00093
Sequence	MRWFLPWTLAAVTAAAASTVLATALSPAPTTMDFTPAPLEDTSSRPQFCKWPCECPPSPP RCPLGVSLITDGCECCKMCAQQLGDNCTEAAICDPHRGLYCDYSGDRPRYAIGVCAQVVG VGCVLDGVRYNNGQSFQPNCKYNCTCIDGAVGCTPLCLRVRPPRLWCPHPRRVSIPGHCC EQWVCEDDAKRPRKTAPRDTGAFDAVGEVEAWHRNCIAYTSPWSPCSTSCGLGVSTRISN VNAQCWPEQESRLCNLRPCDVDIHTLIKAGKKCLAVYQPEASMNFTLAGCISTRSYQPKY CGVCMDNRCCIPYKSKTIDVSFQCPDGLGFSRQVLWINACFCNLSCRNPNDIFADLESYP DFSEIAN
Function	Downstream regulator in the Wnt/Frizzled-signaling pathway. Associated with cell survival. Attenuates p53-mediated apoptosis in response to DNA damage through activation of AKT kinase. Up-regulates the anti-apoptotic Bcl-X(L) protein. Adheres to skin and melanoma fibroblasts. In vitro binding to skin fibroblasts occurs through the proteoglycans, decorin and biglycan.
Tissue Specificity	Expressed in heart, kidney, lung, pancreas, placenta, ovary, small intestine and spleen. Isoform 2 is expressed predominantly in scirrhous gastric carcinoma and, weakly in placenta. Overexpression is associated with several cancers including breast cancer and colon tumors. Isoform 2 is overexpressed in scirrhous gastric carcinoma.
KEGG Pathway	Wnt sig.ling pathway (hsa04310 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Altered Expression	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[9]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[3]
Laryngeal carcinoma	DISNHCIV	Strong	Altered Expression	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[13]
Obesity	DIS47Y1K	Strong	Altered Expression	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[18]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	moderate	Biomarker	[19]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[19]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[20]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[20]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[21]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[22]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[23]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Carcinoma	DISH9F1N	Limited	Altered Expression	[24]
Desmoid tumour	DISGX357	Limited	Altered Expression	[25]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[26]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[23]
Melanoma	DIS1RRCY	Limited	Altered Expression	[27]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[27]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[28]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[26]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[29]
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⏷ Show the Full List of 45 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	CCN family member 4 (CCN4) affects the response to substance of Temozolomide.	[43]
DTI-015	DMXZRW0	Approved	CCN family member 4 (CCN4) affects the response to substance of DTI-015.	[43]
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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 CCN family member 4 (CCN4).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CCN family member 4 (CCN4).	[40]
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13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CCN family member 4 (CCN4).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CCN family member 4 (CCN4).	[32]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of CCN family member 4 (CCN4).	[33]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CCN family member 4 (CCN4).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of CCN family member 4 (CCN4).	[35]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of CCN family member 4 (CCN4).	[36]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of CCN family member 4 (CCN4).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of CCN family member 4 (CCN4).	[37]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of CCN family member 4 (CCN4).	[38]
Calphostin C	DM9X2D0	Terminated	Calphostin C affects the expression of CCN family member 4 (CCN4).	[39]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of CCN family member 4 (CCN4).	[41]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of CCN family member 4 (CCN4).	[42]
U0126	DM31OGF	Investigative	U0126 increases the expression of CCN family member 4 (CCN4).	[36]
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⏷ Show the Full List of 13 Drug(s)

References

1	Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation.Oncotarget. 2015 Mar 20;6(8):6218-34. doi: 10.18632/oncotarget.3358.
2	Associations between WNT1-inducible signaling pathway protein-1 (WISP-1) genetic polymorphisms and clinical aspects of rheumatoid arthritis among Chinese Han subjects.Medicine (Baltimore). 2019 Nov;98(44):e17604. doi: 10.1097/MD.0000000000017604.
3	Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
4	WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma.Cell Death Dis. 2017 Apr 13;8(4):e2750. doi: 10.1038/cddis.2016.421.
5	Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features.Cancer Res. 2001 Dec 15;61(24):8917-23.
6	WISP-1 contributes to fractionated irradiation-induced radioresistance in esophageal carcinoma cell lines and mice.PLoS One. 2014 Apr 11;9(4):e94751. doi: 10.1371/journal.pone.0094751. eCollection 2014.
7	The Effect of Pyrroloquinoline Quinone on the Expression of WISP1 in Traumatic Brain Injury.Stem Cells Int. 2017;2017:4782820. doi: 10.1155/2017/4782820. Epub 2017 Aug 16.
8	Impacts of WNT1-inducible signaling pathway protein 1 polymorphism on hepatocellular carcinoma development.PLoS One. 2018 Jun 11;13(6):e0198967. doi: 10.1371/journal.pone.0198967. eCollection 2018.
9	Association of polymorphisms of SORBS1, GCK and WISP1 with hypertension in community-dwelling Japanese individuals.Hypertens Res. 2009 May;32(5):325-31. doi: 10.1038/hr.2009.23. Epub 2009 Mar 13.
10	Wnt1-inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway.J Cell Physiol. 2019 Sep;234(9):15941-15950. doi: 10.1002/jcp.28253. Epub 2019 Feb 25.
11	Neurotensin Is a Lipid-Induced Gastrointestinal Peptide Associated with Visceral Adipose Tissue Inflammation in Obesity.Nutrients. 2018 Apr 23;10(4):526. doi: 10.3390/nu10040526.
12	Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes.J Cell Commun Signal. 2020 Mar;14(1):101-109. doi: 10.1007/s12079-019-00536-4. Epub 2019 Nov 28.
13	Association of Wnt-Inducible Signaling Pathway Protein 1 Genetic Polymorphisms With Lung Cancer Susceptibility and Platinum-Based Chemotherapy Response.Clin Lung Cancer. 2015 Jul;16(4):298-304.e1-2. doi: 10.1016/j.cllc.2014.12.008. Epub 2014 Dec 30.
14	Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP-1)/CCN4 as a novel biomarker of obesity.J Cell Commun Signal. 2018 Sep;12(3):539-548. doi: 10.1007/s12079-017-0427-1. Epub 2017 Nov 11.
15	Increased WISP1 expression in human osteoarthritic articular cartilage is epigenetically regulated and decreases cartilage matrix production.Rheumatology (Oxford). 2019 Jun 1;58(6):1065-1074. doi: 10.1093/rheumatology/key426.
16	Circ_KATNAL1 regulates prostate cancer cell growth and invasiveness through the miR-145-3p/WISP1 pathway.Biochem Cell Biol. 2020 Jun;98(3):396-404. doi: 10.1139/bcb-2019-0211. Epub 2019 Dec 4.
17	WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts.Sci Rep. 2016 Feb 12;6:20547. doi: 10.1038/srep20547.
18	Dysregulation of -catenin, WISP1 and TCF21 predicts disease-specific survival and primary response against radio(chemo)therapy in patients with locally advanced squamous cell carcinomas of the head and neck.Clin Otolaryngol. 2019 May;44(3):263-272. doi: 10.1111/coa.13281. Epub 2019 Feb 5.
19	Impact of WNT1-inducible signaling pathway protein-1 (WISP-1) genetic polymorphisms and clinical aspects of breast cancer.Medicine (Baltimore). 2019 Nov;98(44):e17854. doi: 10.1097/MD.0000000000017854.
20	Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue.Cell Mol Life Sci. 2018 Jun;75(12):2241-2256. doi: 10.1007/s00018-017-2731-6. Epub 2017 Dec 27.
21	Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
22	Tp53 Mutation Inhibits Ubiquitination and Degradation of WISP1 via Down-Regulation of Siah1 in Pancreatic Carcinogenesis.Front Pharmacol. 2018 Aug 3;9:857. doi: 10.3389/fphar.2018.00857. eCollection 2018.
23	Identification of WISP1 as a novel oncogene in glioblastoma.Int J Oncol. 2017 Oct;51(4):1261-1270. doi: 10.3892/ijo.2017.4119. Epub 2017 Sep 5.
24	A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma.Oncogene. 2001 Sep 6;20(39):5525-32. doi: 10.1038/sj.onc.1204723.
25	Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.Cancer Med. 2014 Feb;3(1):81-90. doi: 10.1002/cam4.160. Epub 2013 Nov 26.
26	Up-regulated Wnt1-inducible signaling pathway protein 1 correlates with poor prognosis and drug resistance by reducing DNA repair in gastric cancer.World J Gastroenterol. 2019 Oct 14;25(38):5814-5825. doi: 10.3748/wjg.v25.i38.5814.
27	WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition.J Biol Chem. 2019 Apr 5;294(14):5261-5280. doi: 10.1074/jbc.RA118.006122. Epub 2019 Feb 5.
28	WNT1-inducible signaling protein-1 mediates TGF-1-induced renal fibrosis in tubular epithelial cells and unilateral ureteral obstruction mouse models via autophagy.J Cell Physiol. 2020 Mar;235(3):2009-2022. doi: 10.1002/jcp.29187. Epub 2019 Sep 11.
29	The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes.Diabetologia. 2018 Sep;61(9):2054-2065. doi: 10.1007/s00125-018-4636-9. Epub 2018 May 12.
30	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.
31	Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
32	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.
33	Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
34	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
35	Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
36	Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
37	Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
38	Effect of indomethacin on Bfl-1, WISP-1 and proliferating cell nuclear antigen in colon cancer cell line HCT116 cells. Chin J Dig Dis. 2006;7(4):219-24. doi: 10.1111/j.1443-9573.2006.00272.x.
39	Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
40	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.
41	Structure-activity relationship of ochratoxin A and synthesized derivatives: importance of amino acid and halogen moiety for cytotoxicity. Arch Toxicol. 2017 Mar;91(3):1461-1471. doi: 10.1007/s00204-016-1799-3. Epub 2016 Jul 15.
42	Wnt-induced secreted proteins-1 play an important role in paraquat-induced pulmonary fibrosis. BMC Pharmacol Toxicol. 2022 Apr 6;23(1):21. doi: 10.1186/s40360-022-00560-y.
43	Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.