Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRFHQ2Z)

DOT Name	Cellular communication network factor 6 (CCN6)
Synonyms	CCN family member 6; WNT1-inducible-signaling pathway protein 3; WISP-3
Gene Name	CCN6
Related Disease	Arthritis ( ) Arthropathy ( ) Autism ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Carcinoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Cardiovascular disease ( ) Colonic neoplasm ( ) Contact dermatitis ( ) Familial hypercholesterolemia ( ) Hypercholesterolemia, familial, 1 ( ) Juvenile idiopathic arthritis ( ) Latent tuberculosis infection ( ) Liver cancer ( ) Meningeal tuberculosis ( ) Mood disorder ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Osteoarthritis ( ) Pancreatic cancer ( ) Polydactyly ( ) Progressive pseudorheumatoid arthropathy of childhood ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary fibrosis ( ) Pulmonary tuberculosis ( ) Rheumatoid arthritis ( ) Schizophrenia ( ) Skeletal system disorder ( ) Spondyloepiphyseal dysplasia congenita ( ) Triple negative breast cancer ( ) Advanced cancer ( ) Chondrosarcoma ( ) Lung neoplasm ( ) Movement disorder ( ) Gastric cancer ( ) Granular corneal dystrophy type II ( ) Hepatocellular carcinoma ( ) Osteochondrodysplasia ( ) Pallister-Hall syndrome ( ) Parkinson disease ( ) Stomach cancer ( )
UniProt ID	CCN6_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00007 ; PF00219 ; PF19035
Sequence	MQGLLFSTLLLAGLAQFCCRVQGTGPLDTTPEGRPGEVSDAPQRKQFCHWPCKCPQQKPR CPPGVSLVRDGCGCCKICAKQPGEICNEADLCDPHKGLYCDYSVDRPRYETGVCAYLVAV GCEFNQVHYHNGQVFQPNPLFSCLCVSGAIGCTPLFIPKLAGSHCSGAKGGKKSDQSNCS LEPLLQQLSTSYKTMPAYRNLPLIWKKKCLVQATKWTPCSRTCGMGISNRVTNENSNCEM RKEKRLCYIQPCDSNILKTIKIPKGKTCQPTFQLSKAEKFVFSGCSSTQSYKPTFCGICL DKRCCIPNKSKMITIQFDCPNEGSFKWKMLWITSCVCQRNCREPGDIFSELKIL
Function	Plays a role in mitochondrial electron transport and mitochondrial respiration. Through its regulation of the mitochondrial function may play a role in normal postnatal skeletal growth and cartilage homeostasis.
Tissue Specificity	Predominant expression in adult kidney and testis and fetal kidney. Weaker expression found in placenta, ovary, prostate and small intestine . Also expressed in skeletally-derived cells such as synoviocytes and articular cartilage chondrocytes .

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Arthritis	DIST1YEL	Strong	Genetic Variation	[1]
Arthropathy	DISVEERK	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[8]
Contact dermatitis	DISQ3AU0	Strong	Genetic Variation	[9]
Familial hypercholesterolemia	DISC06IX	Strong	Biomarker	[7]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[7]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[10]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Meningeal tuberculosis	DIS8KHDE	Strong	Biomarker	[12]
Mood disorder	DISLVMWO	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[16]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[17]
Progressive pseudorheumatoid arthropathy of childhood	DISBMRIW	Strong	Autosomal recessive	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[20]
Pulmonary tuberculosis	DIS6FLUM	Strong	Biomarker	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Skeletal system disorder	DIS5PU87	Strong	Genetic Variation	[2]
Spondyloepiphyseal dysplasia congenita	DISLC6W8	Strong	Genetic Variation	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[24]
Chondrosarcoma	DIS4I7JB	moderate	Biomarker	[25]
Lung neoplasm	DISVARNB	moderate	Biomarker	[26]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[27]
Gastric cancer	DISXGOUK	Limited	Biomarker	[28]
Granular corneal dystrophy type II	DISAEE20	Limited	Biomarker	[29]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[6]
Osteochondrodysplasia	DIS9SPWW	Limited	Genetic Variation	[30]
Pallister-Hall syndrome	DISTYTPU	Limited	Biomarker	[31]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[32]
Stomach cancer	DISKIJSX	Limited	Biomarker	[28]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cellular communication network factor 6 (CCN6).	[33]
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References

1	Progressive Pseudorheumatoid Dysplasia resolved by whole exome sequencing: a novel mutation in WISP3 and review of the literature.BMC Med Genet. 2019 Mar 29;20(1):53. doi: 10.1186/s12881-019-0787-x.
2	A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy.J Pediatr Endocrinol Metab. 2011;24(1-2):105-8. doi: 10.1515/jpem.2011.117.
3	Molecular and cytogenetic analyses on Brazilian youths with pervasive developmental disorders.J Autism Dev Disord. 2002 Feb;32(1):35-41. doi: 10.1023/a:1017952123258.
4	Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas.J Cell Commun Signal. 2018 Mar;12(1):13-19. doi: 10.1007/s12079-018-0451-9. Epub 2018 Jan 22.
5	Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1.Am J Pathol. 2008 Apr;172(4):893-904. doi: 10.2353/ajpath.2008.070899. Epub 2008 Mar 5.
6	Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of -catenin/TCF/LEF signalling.Cell Prolif. 2019 May;52(3):e12583. doi: 10.1111/cpr.12583. Epub 2019 Feb 22.
7	Genotype of the mutant LDL receptor allele is associated with LDL particle size heterogeneity in familial hypercholesterolemia.Atherosclerosis. 2006 Jan;184(1):163-70. doi: 10.1016/j.atherosclerosis.2005.03.027.
8	WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14717-22. doi: 10.1073/pnas.95.25.14717.
9	The specificity of a nickel sulphate reaction in vitro: a family study and a study of chromium-allergic subjects.Scand J Immunol. 1981;13(3):231-5. doi: 10.1111/j.1365-3083.1981.tb00130.x.
10	Wnt-1-inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis.Arthritis Rheum. 2005 Nov;52(11):3548-53. doi: 10.1002/art.21392.
11	Is latent tuberculosis infection challenging in Iranian health care workers? A systematic review and meta-analysis.PLoS One. 2019 Oct 3;14(10):e0223335. doi: 10.1371/journal.pone.0223335. eCollection 2019.
12	DNA polymorphism of Mycobacterium tuberculosis PE_PGRS33 gene among clinical isolates of pediatric TB patients and its associations with clinical presentation.Tuberculosis (Edinb). 2011 Jul;91(4):287-92. doi: 10.1016/j.tube.2011.05.001. Epub 2011 Jun 12.
13	Schizotypal and paranoid personality disorder in the relatives of patients with schizophrenia and affective disorders: a review.Schizophr Res. 1993 Dec;11(1):81-92. doi: 10.1016/0920-9964(93)90041-g.
14	The effects and mechanisms of a biosynthetic ginsenoside 3,12-Di-O-Glc-PPD on non-small cell lung cancer.Onco Targets Ther. 2019 Sep 9;12:7375-7385. doi: 10.2147/OTT.S217039. eCollection 2019.
15	Expression profiles of human CCN genes in patients with osteoarthritis or rheumatoid arthritis.J Orthop Sci. 2015 Jul;20(4):708-16. doi: 10.1007/s00776-015-0727-3. Epub 2015 May 19.
16	Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: anticancer activity and mechanisms of action.Cancer Lett. 2009 Jun 18;278(2):241-248. doi: 10.1016/j.canlet.2009.01.005. Epub 2009 Feb 8.
17	A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly.Hum Mol Genet. 2003 Jul 15;12(14):1725-35. doi: 10.1093/hmg/ddg180.
18	Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet. 1999 Sep;23(1):94-8. doi: 10.1038/12699.
19	20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action.Br J Cancer. 2008 Feb 26;98(4):792-802. doi: 10.1038/sj.bjc.6604227. Epub 2008 Feb 5.
20	WISP3 prevents fibroblast-myofibroblast transdifferentiation in NRK-49F cells.Biomed Pharmacother. 2018 Mar;99:306-312. doi: 10.1016/j.biopha.2018.01.005.
21	Influence of HLA-DR and -DO phenotypes on tuberculin reactive status in pulmonary tuberculosis patients.Tuber Lung Dis. 1996 Aug;77(4):369-73. doi: 10.1016/s0962-8479(96)90104-5.
22	Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type. Hum Mutat. 2015 Oct;36(10):1004-8. doi: 10.1002/humu.22839. Epub 2015 Aug 6.
23	CCN6 regulates IGF2BP2and HMGA2 signaling in metaplastic carcinomas of the breast.Breast Cancer Res Treat. 2018 Dec;172(3):577-586. doi: 10.1007/s10549-018-4960-2. Epub 2018 Sep 15.
24	4-XL-PPD, a novel ginsenoside derivative, as potential therapeutic agents for gastric cancer shows anti-cancer activity via inducing cell apoptosis medicated generation of reactive oxygen species and inhibiting migratory and invasive.Biomed Pharmacother. 2019 Oct;118:108589. doi: 10.1016/j.biopha.2019.01.050. Epub 2019 Aug 2.
25	CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma.Cell Death Dis. 2018 Sep 20;9(10):955. doi: 10.1038/s41419-018-1008-9.
26	Oligogenic germline mutations identified in early non-smokers lung adenocarcinoma patients.Lung Cancer. 2014 Aug;85(2):168-74. doi: 10.1016/j.lungcan.2014.05.020. Epub 2014 Jun 4.
27	WISP3 mutation associated with pseudorheumatoid dysplasia.Cold Spring Harb Mol Case Stud. 2018 Feb 1;4(1):a001990. doi: 10.1101/mcs.a001990. Print 2018 Feb.
28	Antitumor activity of ginseng sapogenins, 25-OH-PPD and 25-OCH3-PPD, on gastric cancer cells.Biotechnol Lett. 2016 Jan;38(1):43-50. doi: 10.1007/s10529-015-1964-4. Epub 2015 Oct 1.
29	Screening for skin-sensitizing allergens among patients with clinically suspected allergic contact dermatitis.Saudi Med J. 2017 Sep;38(9):922-927. doi: 10.15537/smj.2017.9.19864.
30	Mutant WISP3 triggers the phenotype shift of articular chondrocytes by promoting sensitivity to IGF-1 hypothesis of spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA).Med Hypotheses. 2007;68(6):1406-10. doi: 10.1016/j.mehy.2006.06.046. Epub 2007 Mar 23.
31	Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations.J Appl Genet. 2012 Nov;53(4):415-22. doi: 10.1007/s13353-012-0109-x. Epub 2012 Aug 18.
32	Genetic analysis of the FBXO48 gene in Chinese Han patients with Parkinson disease.Neurosci Lett. 2013 Apr 29;541:224-6. doi: 10.1016/j.neulet.2013.02.031. Epub 2013 Feb 26.
33	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.