Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOW5YL4)

• DOT Name: CCN family member 3 (CCN3)
• Synonyms: Cellular communication network factor 3; Insulin-like growth factor-binding protein 9; IBP-9; IGF-binding protein 9; IGFBP-9; Nephro blastoma-overexpressed gene protein homolog; Protein NOV homolog; NovH
• Gene Name: CCN3
• Related Disease:
  Chronic kidney disease
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast neoplasm
  Cardiac failure
  Castration-resistant prostate carcinoma
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Congestive heart failure
  Epilepsy
  Epithelial ovarian cancer
  Ewing sarcoma
  Gastric cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Liver cirrhosis
  Metastatic malignant neoplasm
  Neoplasm
  Nephropathy
  Non-alcoholic fatty liver disease
  Osteoarthritis
  Pancreatic cancer
  Rhabdomyosarcoma
  Sarcoma
  Stomach cancer
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
  Colorectal carcinoma
  Melanoma
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Abdominal aortic aneurysm
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Glomerulonephritis
  Hyperglycemia
  Multiple sclerosis
  Obesity
  Renal cell carcinoma
• UniProt ID: CCN3_HUMAN
• Pfam ID: PF00007 ; PF00219 ; PF19035 ; PF00093
• Sequence:
  MQSVQSTSFCLRKQCLCLTFLLLHLLGQVAATQRCPPQCPGRCPATPPTCAPGVRAVLDG
  CSCCLVCARQRGESCSDLEPCDESSGLYCDRSADPSNQTGICTAVEGDNCVFDGVIYRSG
  EKFQPSCKFQCTCRDGQIGCVPRCQLDVLLPEPNCPAPRKVEVPGECCEKWICGPDEEDS
  LGGLTLAAYRPEATLGVEVSDSSVNCIEQTTEWTACSKSCGMGFSTRVTNRNRQCEMLKQ
  TRLCMVRPCEQEPEQPTDKKGKKCLRTKKSLKAIHLQFKNCTSLHTYKPRFCGVCSDGRC
  CTPHNTKTIQAEFQCSPGQIVKKPVMVIGTCTCHTNCPKNNEAFLQELELKTTRGKM
• Function: Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival. Acts by binding to integrins or membrane receptors such as NOTCH1. Essential regulator of hematopoietic stem and progenitor cell function. Inhibits myogenic differentiation through the activation of Notch-signaling pathway. Inhibits vascular smooth muscle cells proliferation by increasing expression of cell-cycle regulators such as CDKN2B or CDKN1A independently of TGFB1 signaling. Ligand of integrins ITGAV:ITGB3 and ITGA5:ITGB1, acts directly upon endothelial cells to stimulate pro-angiogenic activities and induces angiogenesis. In endothelial cells, supports cell adhesion, induces directed cell migration (chemotaxis) and promotes cell survival. Also plays a role in cutaneous wound healing acting as integrin receptor ligand. Supports skin fibroblast adhesion through ITGA5:ITGB1 and ITGA6:ITGB1 and induces fibroblast chemotaxis through ITGAV:ITGB5. Seems to enhance bFGF-induced DNA synthesis in fibroblasts. Involved in bone regeneration as a negative regulator. Enhances the articular chondrocytic phenotype, whereas it repressed the one representing endochondral ossification. Impairs pancreatic beta-cell function, inhibits beta-cell proliferation and insulin secretion. Plays a role as negative regulator of endothelial pro-inflammatory activation reducing monocyte adhesion, its anti-inflammatory effects occur secondary to the inhibition of NF-kappaB signaling pathway. Contributes to the control and coordination of inflammatory processes in atherosclerosis. Attenuates inflammatory pain through regulation of IL1B- and TNF-induced MMP9, MMP2 and CCL2 expression. Inhibits MMP9 expression through ITGB1 engagement.
• Tissue Specificity: Expressed in endiothelial cells (at protein level) . Expressed in bone marrow, thymic cells and nephroblastoma. Increased expression in Wilms tumor of the stromal type.

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Altered Expression	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[9]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[10]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[11]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[8]
Epilepsy	DISBB28L	Strong	Genetic Variation	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[13]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[14]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[15]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Nephropathy	DISXWP4P	Strong	Altered Expression	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Biomarker	[19]
Rhabdomyosarcoma	DISNR7MS	Strong	Genetic Variation	[20]
Sarcoma	DISZDG3U	Strong	Altered Expression	[21]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[15]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[8]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[6]
Wilms tumor	DISB6T16	Strong	Biomarker	[22]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[4]
Melanoma	DIS1RRCY	moderate	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Altered Expression	[24]
Prostate cancer	DISF190Y	moderate	Biomarker	[25]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[25]
Endometrial cancer	DISW0LMR	Disputed	Biomarker	[26]
Endometrial carcinoma	DISXR5CY	Disputed	Biomarker	[26]
Abdominal aortic aneurysm	DISD06OF	Limited	Biomarker	[27]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[28]
Breast cancer	DIS7DPX1	Limited	Biomarker	[29]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[29]
Glomerulonephritis	DISPZIQ3	Limited	Biomarker	[30]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[31]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[32]
Obesity	DIS47Y1K	Limited	Altered Expression	[24]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of CCN family member 3 (CCN3).	[33]

17 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 3 (CCN3).	[34]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of CCN family member 3 (CCN3).	[35]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of CCN family member 3 (CCN3).	[36]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of CCN family member 3 (CCN3).	[37]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CCN family member 3 (CCN3).	[38]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of CCN family member 3 (CCN3).	[39]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of CCN family member 3 (CCN3).	[35]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of CCN family member 3 (CCN3).	[40]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of CCN family member 3 (CCN3).	[41]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of CCN family member 3 (CCN3).	[42]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of CCN family member 3 (CCN3).	[43]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of CCN family member 3 (CCN3).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of CCN family member 3 (CCN3).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CCN family member 3 (CCN3).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of CCN family member 3 (CCN3).	[46]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of CCN family member 3 (CCN3).	[47]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of CCN family member 3 (CCN3).	[35]

References

• [1] Urinary mRNA expression of CCN2/CCN3 as a noninvasive marker for monitoring glomerular structure changes in nondiabetic chronic kidney disease.Biomarkers. 2012 Dec;17(8):714-20. doi: 10.3109/1354750X.2012.722229. Epub 2012 Oct 15.
• [2] Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues.Mol Pathol. 2001 Aug;54(4):275-80. doi: 10.1136/mp.54.4.275.
• [3] NOVH increases MMP3 expression and cell migration in glioblastoma cells via a PDGFR-alpha-dependent mechanism.FASEB J. 2003 Oct;17(13):1919-21. doi: 10.1096/fj.02-1023fje. Epub 2003 Aug 15.
• [4] Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.Oncotarget. 2017 Apr 18;8(16):26231-26244. doi: 10.18632/oncotarget.15439.
• [5] CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis.Am J Pathol. 2017 Jun;187(6):1230-1237. doi: 10.1016/j.ajpath.2017.01.020.
• [6] NOV is upregulated and promotes migration and invasion in bladder cancer.Tumour Biol. 2014 Jul;35(7):6749-55. doi: 10.1007/s13277-014-1919-8. Epub 2014 Apr 10.
• [7] 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.
• [8] Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes.J Cell Commun Signal. 2018 Mar;12(1):359-368. doi: 10.1007/s12079-018-0458-2. Epub 2018 Feb 6.
• [9] CCN3-EZH2-AR feedback loop: new targets for enzalutamide and castration resistant prostate cancer.J Cell Commun Signal. 2017 Mar;11(1):89-91. doi: 10.1007/s12079-017-0378-6. Epub 2017 Mar 2.
• [10] The clinical and prognostic significance of CCN3 expression in patients with cervical cancer.Adv Clin Exp Med. 2013 Nov-Dec;22(6):839-45.
• [11] Nephroblastoma overexpressed gene expression and its prognostic implications of clinical outcomes in renal cell carcinoma patients.Cancer Biomark. 2017 Sep 7;20(3):241-246. doi: 10.3233/CBM-170017.
• [12] Whole exome sequencing reveals novel NOV and DCAF13 variants in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy.Neurosci Lett. 2018 Sep 25;684:115-120. doi: 10.1016/j.neulet.2018.07.014. Epub 2018 Jul 9.
• [13] Expression profiles of 290 ESTs mapped to chromosome 3 in human epithelial ovarian cancer cell lines using DNA expression oligonucleotide microarrays.Genome Res. 2002 Jan;12(1):112-21. doi: 10.1101/gr.174202.
• [14] Prognostic relevance of CCN3 in Ewing sarcoma.Hum Pathol. 2009 Oct;40(10):1479-86. doi: 10.1016/j.humpath.2009.05.008. Epub 2009 Aug 19.
• [15] Differential expression of CCN family members CYR611, CTGF and NOV in gastric cancer and their association with disease progression.Oncol Rep. 2016 Nov;36(5):2517-2525. doi: 10.3892/or.2016.5074. Epub 2016 Sep 8.
• [16] Paracrine effects of CCN3 from non-cancerous hepatic cells increase signaling and progression of hepatocellular carcinoma.BMC Cancer. 2019 Apr 27;19(1):395. doi: 10.1186/s12885-019-5603-7.
• [17] Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?.Cell Commun Signal. 2019 Apr 23;17(1):38. doi: 10.1186/s12964-019-0350-6.
• [18] NOV/CCN3 induces cartilage protection by inhibiting PI3K/AKT/mTOR pathway.J Cell Mol Med. 2019 Nov;23(11):7525-7534. doi: 10.1111/jcmm.14621. Epub 2019 Aug 27.
• [19] NOV promoted the growth and migration of pancreatic cancer cells.Tumour Biol. 2014 Apr;35(4):3195-201. doi: 10.1007/s13277-013-1418-3. Epub 2013 Nov 21.
• [20] Nephroblastoma overexpressed (NOV/CCN3) gene: a paired-domain-specific PAX3-FKHR transcription target that promotes survival and motility in alveolar rhabdomyosarcoma cells.Oncogene. 2011 Aug 11;30(32):3549-62. doi: 10.1038/onc.2011.69. Epub 2011 Mar 21.
• [21] In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type.Oncogene. 2005 Jun 23;24(27):4349-61. doi: 10.1038/sj.onc.1208620.
• [22] NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia.J Pathol. 2003 Dec;201(4):609-15. doi: 10.1002/path.1468.
• [23] Downregulation of CCN3 expression as a potential mechanism for melanoma progression.Oncogene. 2008 Apr 17;27(18):2552-60. doi: 10.1038/sj.onc.1210896. Epub 2007 Oct 29.
• [24] Serum CCN3 levels are increased in type 2 diabetes mellitus and associated with obesity, insulin resistance and inflammation.Clin Chim Acta. 2019 Jul;494:52-57. doi: 10.1016/j.cca.2019.03.006. Epub 2019 Mar 13.
• [25] CCN3/Nephroblastoma Overexpressed Is a Functional Mediator of Prostate Cancer Bone Metastasis That Is Associated with Poor Patient Prognosis.Am J Pathol. 2019 Jul;189(7):1451-1461. doi: 10.1016/j.ajpath.2019.04.006. Epub 2019 Jun 12.
• [26] Cyr61, a member of ccn (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family, predicts survival of patients with endometrial cancer of endometrioid subtype.Gynecol Oncol. 2009 Jan;112(1):229-34. doi: 10.1016/j.ygyno.2008.09.039. Epub 2008 Nov 12.
• [27] CCN3: stopping that achy, breaky aorta.J Cell Commun Signal. 2017 Mar;11(1):93-94. doi: 10.1007/s12079-016-0363-5. Epub 2016 Nov 12.
• [28] A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation.Blood. 2006 Sep 1;108(5):1716-23. doi: 10.1182/blood-2006-04-016113. Epub 2006 May 2.
• [29] Osteoblasts are "educated" by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment.Breast Cancer Res. 2019 Feb 27;21(1):31. doi: 10.1186/s13058-019-1117-0.
• [30] A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects.Am J Pathol. 2012 May;180(5):1979-90. doi: 10.1016/j.ajpath.2012.01.031.
• [31] Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities.Hum Genomics. 2015 Sep 23;9:24. doi: 10.1186/s40246-015-0046-y.
• [32] Characterization of human NOV in biological fluids: an enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system.J Clin Endocrinol Metab. 2003 Jan;88(1):327-36. doi: 10.1210/jc.2002-020304.
• [33] 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.
• [34] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [35] Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. J Mol Endocrinol. 2004 Apr;32(2):397-414.
• [36] 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.
• [37] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [38] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [39] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [40] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [41] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [42] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [43] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [44] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [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] 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.