Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD2CYM5)

• DOT Name: Cadherin-13 (CDH13)
• Synonyms: Heart cadherin; H-cadherin; P105; Truncated cadherin; T-cad; T-cadherin
• Gene Name: CDH13
• Related Disease:
  Glioblastoma multiforme
  Lung cancer
  Adenoma
  Advanced cancer
  Alcohol dependence
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cervical carcinoma
  Colon cancer
  Colorectal carcinoma
  Coronary heart disease
  Crohn disease
  Depression
  Drug dependence
  Erectile dysfunction
  Gastric cancer
  Glioma
  High blood pressure
  Lung neoplasm
  Malaria
  Non-small-cell lung cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate neoplasm
  Schizophrenia
  Squamous cell carcinoma
  Substance abuse
  Substance dependence
  Stomach cancer
  Melanoma
  Acute myelogenous leukaemia
  Chronic obstructive pulmonary disease
  Endometrial carcinoma
  Esophageal cancer
  Hepatocellular carcinoma
  Hypothyroidism
  Neoplasm of esophagus
  Prostate cancer
• UniProt ID: CAD13_HUMAN
• PDB ID: 2V37
• Pfam ID: PF00028 ; PF08758
• Sequence:
  MQPRTPLVLCVLLSQVLLLTSAEDLDCTPGFQQKVFHINQPAEFIEDQSILNLTFSDCKG
  NDKLRYEVSSPYFKVNSDGGLVALRNITAVGKTLFVHARTPHAEDMAELVIVGGKDIQGS
  LQDIFKFARTSPVPRQKRSIVVSPILIPENQRQPFPRDVGKVVDSDRPERSKFRLTGKGV
  DQEPKGIFRINENTGSVSVTRTLDREVIAVYQLFVETTDVNGKTLEGPVPLEVIVIDQND
  NRPIFREGPYIGHVMEGSPTGTTVMRMTAFDADDPATDNALLRYNIRQQTPDKPSPNMFY
  IDPEKGDIVTVVSPALLDRETLENPKYELIIEAQDMAGLDVGLTGTATATIMIDDKNDHS
  PKFTKKEFQATVEEGAVGVIVNLTVEDKDDPTTGAWRAAYTIINGNPGQSFEIHTNPQTN
  EGMLSVVKPLDYEISAFHTLLIKVENEDPLVPDVSYGPSSTATVHITVLDVNEGPVFYPD
  PMMVTRQEDLSVGSVLLTVNATDPDSLQHQTIRYSVYKDPAGWLNINPINGTVDTTAVLD
  RESPFVDNSVYTALFLAIDSGNPPATGTGTLLITLEDVNDNAPFIYPTVAEVCDDAKNLS
  VVILGASDKDLHPNTDPFKFEIHKQAVPDKVWKISKINNTHALVSLLQNLNKANYNLPIM
  VTDSGKPPMTNITDLRVQVCSCRNSKVDCNAAGALRFSLPSVLLLSLFSLACL
• Function: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. May act as a negative regulator of neural cell growth.
• Tissue Specificity: Highly expressed in heart. In the CNS, expressed in cerebral cortex, medulla, hippocampus, amygdala, thalamus and substantia nigra. No expression detected in cerebellum or spinal cord.
• Reactome Pathway: Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[4]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[7]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[8]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[10]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[10]
Carcinoma	DISH9F1N	Strong	Altered Expression	[11]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[4]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[14]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[15]
Depression	DIS3XJ69	Strong	Altered Expression	[7]
Drug dependence	DIS9IXRC	Strong	Biomarker	[16]
Erectile dysfunction	DISD8MTH	Strong	Genetic Variation	[17]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[20]
Lung neoplasm	DISVARNB	Strong	Biomarker	[21]
Malaria	DISQ9Y50	Strong	Genetic Variation	[22]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[23]
Obesity	DIS47Y1K	Strong	Altered Expression	[24]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[25]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[25]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[26]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[27]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[28]
Substance abuse	DIS327VW	Strong	Biomarker	[29]
Substance dependence	DISDRAAR	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	moderate	Biomarker	[30]
Melanoma	DIS1RRCY	Disputed	Biomarker	[31]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[32]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[33]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[34]
Esophageal cancer	DISGB2VN	Limited	Altered Expression	[35]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[36]
Hypothyroidism	DISR0H6D	Limited	Genetic Variation	[37]
Neoplasm of esophagus	DISOLKAQ	Limited	Altered Expression	[35]
Prostate cancer	DISF190Y	Limited	Posttranslational Modification	[38]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Cadherin-13 (CDH13) affects the response to substance of Estradiol.	[51]
DTI-015	DMXZRW0	Approved	Cadherin-13 (CDH13) affects the response to substance of DTI-015.	[52]
Methamphetamine	DMPM4SK	Approved	Cadherin-13 (CDH13) affects the response to substance of Methamphetamine.	[53]
Daunorubicin	DMQUSBT	Approved	Cadherin-13 (CDH13) affects the response to substance of Daunorubicin.	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cadherin-13 (CDH13).	[39]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cadherin-13 (CDH13).	[40]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cadherin-13 (CDH13).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cadherin-13 (CDH13).	[42]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cadherin-13 (CDH13).	[43]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-13 (CDH13).	[44]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cadherin-13 (CDH13).	[46]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Cadherin-13 (CDH13).	[47]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cadherin-13 (CDH13).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine decreases the methylation of Cadherin-13 (CDH13).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cadherin-13 (CDH13).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cadherin-13 (CDH13).	[50]

References

• [1] NFKB1: a suppressor of inflammation, ageing and cancer.FEBS J. 2016 May;283(10):1812-22. doi: 10.1111/febs.13627. Epub 2016 Jan 13.
• [2] CDH13 promoter methylation regulates cisplatin resistance of non-small cell lung cancer cells.Oncol Lett. 2018 Nov;16(5):5715-5722. doi: 10.3892/ol.2018.9325. Epub 2018 Aug 20.
• [3] Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas.Mod Pathol. 2007 Dec;20(12):1269-77. doi: 10.1038/modpathol.3800965. Epub 2007 Sep 14.
• [4] Aberrant Methylation of T-cadherin Can Be a Diagnostic Biomarker for Colorectal Cancer.Cancer Genomics Proteomics. 2017 Jul-Aug;14(4):277-284. doi: 10.21873/cgp.20038.
• [5] Genome-wide association study of comorbid depressive syndrome and alcohol dependence.Psychiatr Genet. 2012 Feb;22(1):31-41. doi: 10.1097/YPG.0b013e32834acd07.
• [6] Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer's disease.Eur Rev Med Pharmacol Sci. 2018 May;22(9):2801-2808. doi: 10.26355/eurrev_201805_14979.
• [7] Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:158-168. doi: 10.1016/j.pnpbp.2018.08.010. Epub 2018 Aug 28.
• [8] Conditional deletion of Cadherin 13 perturbs Golgi cells and disrupts social and cognitive behaviors.Genes Brain Behav. 2018 Jul;17(6):e12466. doi: 10.1111/gbb.12466. Epub 2018 Mar 15.
• [9] Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors.Int J Cancer. 2008 Nov 15;123(10):2331-6. doi: 10.1002/ijc.23804.
• [10] A Systematic Analysis of the Relationship of CDH13 Promoter Methylation and Breast Cancer Risk and Prognosis.PLoS One. 2016 May 6;11(5):e0149185. doi: 10.1371/journal.pone.0149185. eCollection 2016.
• [11] BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells.Lab Invest. 2012 Dec;92(12):1788-800. doi: 10.1038/labinvest.2012.140. Epub 2012 Oct 15.
• [12] Revealing the Strong Functional Association of adipor2 and cdh13 with adipoq: A Gene Network Study.Cell Biochem Biophys. 2015 Apr;71(3):1445-56. doi: 10.1007/s12013-014-0367-9.
• [13] Correlation between T-cadherin gene expression and aberrant methylation of T-cadherin promoter in human colon carcinoma cells.Med Oncol. 2012 Jun;29(2):915-8. doi: 10.1007/s12032-011-9836-9. Epub 2011 Feb 5.
• [14] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [15] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [16] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [17] GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.Am J Hum Genet. 2019 Jan 3;104(1):157-163. doi: 10.1016/j.ajhg.2018.11.004. Epub 2018 Dec 21.
• [18] Methylation pattern of CDH13 gene in digestive tract cancers.Br J Cancer. 2004 Sep 13;91(6):1139-42. doi: 10.1038/sj.bjc.6602095.
• [19] Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid-guided resection of glioma.J Neurosurg. 2013 Nov;119(5):1331-9. doi: 10.3171/2013.7.JNS122340. Epub 2013 Sep 6.
• [20] Interactions of CDH13 gene polymorphisms and ambient PM(10) air pollution exposure with blood pressure and hypertension in Korean men.Chemosphere. 2019 Mar;218:292-298. doi: 10.1016/j.chemosphere.2018.11.125. Epub 2018 Nov 20.
• [21] DNA methylation markers and early recurrence in stage I lung cancer.N Engl J Med. 2008 Mar 13;358(11):1118-28. doi: 10.1056/NEJMoa0706550.
• [22] Imputation-based meta-analysis of severe malaria in three African populations.PLoS Genet. 2013 May;9(5):e1003509. doi: 10.1371/journal.pgen.1003509. Epub 2013 May 23.
• [23] Methylation of RASSF1A and CDH13 genes in individualized chemotherapy for patients with non-small cell lung cancer.Asian Pac J Cancer Prev. 2014;15(12):4925-8. doi: 10.7314/apjcp.2014.15.12.4925.
• [24] CDH13 abundance interferes with adipocyte differentiation and is a novel biomarker for adipose tissue health.Int J Obes (Lond). 2018 Jun;42(5):1039-1050. doi: 10.1038/s41366-018-0022-4. Epub 2018 Feb 21.
• [25] Importance of Cadherins Methylation in Ovarian Cancer: a Next Generation Sequencing Approach.Pathol Oncol Res. 2019 Oct;25(4):1457-1465. doi: 10.1007/s12253-018-0500-y. Epub 2018 Oct 27.
• [26] Multiple loci identified in a genome-wide association study of prostate cancer.Nat Genet. 2008 Mar;40(3):310-5. doi: 10.1038/ng.91. Epub 2008 Feb 10.
• [27] Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.Mol Psychiatry. 2014 Mar;19(3):325-33. doi: 10.1038/mp.2013.2. Epub 2013 Jan 29.
• [28] T-cadherin enhances cell-matrix adhesiveness by regulating beta1 integrin trafficking in cutaneous squamous carcinoma cells.Genes Cells. 2007 Jun;12(6):787-96. doi: 10.1111/j.1365-2443.2007.01092.x.
• [29] Genetic background of extreme violent behavior.Mol Psychiatry. 2015 Jun;20(6):786-92. doi: 10.1038/mp.2014.130. Epub 2014 Oct 28.
• [30] Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay.Int J Cancer. 2002 Apr 20;98(6):833-7. doi: 10.1002/ijc.10257.
• [31] Loss of T-cadherin (CDH-13) regulates AKT signaling and desensitizes cells to apoptosis in melanoma.Mol Carcinog. 2014 Aug;53(8):635-47. doi: 10.1002/mc.22018. Epub 2013 Apr 26.
• [32] 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.
• [33] A genome-wide analysis of the response to inhaled 2-agonists in chronic obstructive pulmonary disease.Pharmacogenomics J. 2016 Aug;16(4):326-35. doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.
• [34] Combining copy number, methylation markers, and mutations as a panel for endometrial cancer detection via intravaginal tampon collection.Gynecol Oncol. 2020 Feb;156(2):387-392. doi: 10.1016/j.ygyno.2019.11.028. Epub 2019 Nov 28.
• [35] Correlations of Promoter Methylation in WIF-1, RASSF1A, and CDH13 Genes with the Risk and Prognosis of Esophageal Cancer.Med Sci Monit. 2016 Aug 10;22:2816-24. doi: 10.12659/msm.896877.
• [36] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [37] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [38] Aberrant promoter methylation of the cadherin 13 gene in serum and its relationship with clinicopathological features of prostate cancer.J Int Med Res. 2014 Oct;42(5):1085-92. doi: 10.1177/0300060514540631. Epub 2014 Jul 11.
• [39] 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.
• [40] 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.
• [41] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [42] 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.
• [43] 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.
• [44] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [45] Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Blood. 2008 Feb 15;111(4):2382-4. doi: 10.1182/blood-2007-07-103960. Epub 2007 Nov 30.
• [46] Impact of extracellular folate levels on global gene expression. Mol Pharmacol. 2001 Dec;60(6):1288-95. doi: 10.1124/mol.60.6.1288.
• [47] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [48] 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.
• [49] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [50] 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.
• [51] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.
• [52] 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.
• [53] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
• [54] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.