Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8LH3HN)

• DOT Name: Cadherin-4 (CDH4)
• Synonyms: Retinal cadherin; R-CAD; R-cadherin
• Gene Name: CDH4
• Related Disease:
  Advanced cancer
  Bone osteosarcoma
  Carcinoma
  Colorectal carcinoma
  Coronary heart disease
  Digestive system neoplasm
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Immunodeficiency
  Obstructive sleep apnea
  Osteosarcoma
  Sarcoidosis
  Stomach cancer
  Nasopharyngeal carcinoma
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Multiple congenital anomalies/dysmorphic syndrome
  Neoplasm
• UniProt ID: CADH4_HUMAN
• Pfam ID: PF01049 ; PF00028 ; PF08758
• Sequence:
  MTAGAGVLLLLLSLSGALRAHNEDLTTRETCKAGFSEDDYTALISQNILEGEKLLQVKFS
  SCVGTKGTQYETNSMDFKVGADGTVFATRELQVPSEQVAFTVTAWDSQTAEKWDAVVRLL
  VAQTSSPHSGHKPQKGKKVVALDPSPPPKDTLLPWPQHQNANGLRRRKRDWVIPPINVPE
  NSRGPFPQQLVRIRSDKDNDIPIRYSITGVGADQPPMEVFSIDSMSGRMYVTRPMDREEH
  ASYHLRAHAVDMNGNKVENPIDLYIYVIDMNDNRPEFINQVYNGSVDEGSKPGTYVMTVT
  ANDADDSTTANGMVRYRIVTQTPQSPSQNMFTINSETGDIVTVAAGLDREKVQQYTVIVQ
  ATDMEGNLNYGLSNTATAIITVTDVNDNPPEFTASTFAGEVPENRVETVVANLTVMDRDQ
  PHSPNWNAVYRIISGDPSGHFSVRTDPVTNEGMVTVVKAVDYELNRAFMLTVMVSNQAPL
  ASGIQMSFQSTAGVTISIMDINEAPYFPSNHKLIRLEEGVPPGTVLTTFSAVDPDRFMQQ
  AVRYSKLSDPASWLHINATNGQITTAAVLDRESLYTKNNVYEATFLAADNGIPPASGTGT
  LQIYLIDINDNAPELLPKEAQICEKPNLNAINITAADADVDPNIGPYVFELPFVPAAVRK
  NWTITRLNGDYAQLSLRILYLEAGMYDVPIIVTDSGNPPLSNTSIIKVKVCPCDDNGDCT
  TIGAVAAAGLGTGAIVAILICILILLTMVLLFVMWMKRREKERHTKQLLIDPEDDVRDNI
  LKYDEEGGGEEDQDYDLSQLQQPEAMGHVPSKAPGVRRVDERPVGAEPQYPIRPMVPHPG
  DIGDFINEGLRAADNDPTAPPYDSLLVFDYEGSGSTAGSVSSLNSSSSGDQDYDYLNDWG
  PRFKKLADMYGGGEED
• 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 play an important role in retinal development.
• Tissue Specificity: Expressed mainly in brain but also found in other tissues.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Myogenesis (R-HSA-525793)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Posttranslational Modification	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[4]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[5]
Digestive system neoplasm	DISPOJCT	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Immunodeficiency	DIS093I0	Strong	Biomarker	[1]
Obstructive sleep apnea	DIS0SVD1	Strong	Genetic Variation	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[8]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[3]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Posttranslational Modification	[9]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[10]
Lung cancer	DISCM4YA	Limited	Biomarker	[11]
Lung carcinoma	DISTR26C	Limited	Biomarker	[11]
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Limited	Autosomal recessive	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Cadherin-4 (CDH4) increases the Bone disorder ADR of Dexamethasone.	[27]

3 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 Cadherin-4 (CDH4).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cadherin-4 (CDH4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cadherin-4 (CDH4).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cadherin-4 (CDH4).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cadherin-4 (CDH4).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cadherin-4 (CDH4).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cadherin-4 (CDH4).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cadherin-4 (CDH4).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Cadherin-4 (CDH4).	[20]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Cadherin-4 (CDH4).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cadherin-4 (CDH4).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cadherin-4 (CDH4).	[24]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Cadherin-4 (CDH4).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cadherin-4 (CDH4).	[26]

References

• [1] Cdh4 Down-Regulation Impairs in Vivo Infiltration and Malignancy in Patients Derived Glioblastoma Cells.Int J Mol Sci. 2019 Aug 18;20(16):4028. doi: 10.3390/ijms20164028.
• [2] CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis.Oncogene. 2018 Jul;37(27):3617-3630. doi: 10.1038/s41388-018-0231-2. Epub 2018 Apr 3.
• [3] Frequent aberrant methylation of the CDH4 gene promoter in human colorectal and gastric cancer.Cancer Res. 2004 Nov 15;64(22):8156-9. doi: 10.1158/0008-5472.CAN-04-3000.
• [4] Comparative detection of aberrantly methylated DNA in preoperative and postoperative stool from patients with colorectal cancers.Int J Biol Markers. 2015 Jan-Mar;30(1):e81-7. doi: 10.5301/jbm.5000099.
• [5] Discrepancy between the European clinical guidelines and myocardial revascularization in patients with stable coronary artery disease in Russia.Int J Qual Health Care. 2019 May 1;31(4):269-275. doi: 10.1093/intqhc/mzy140.
• [6] Long non-coding RNA linc-cdh4-2 inhibits the migration and invasion of HCC cells by targeting R-cadherin pathway.Biochem Biophys Res Commun. 2016 Nov 18;480(3):348-354. doi: 10.1016/j.bbrc.2016.10.048. Epub 2016 Oct 17.
• [7] Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans.Am J Respir Crit Care Med. 2016 Oct 1;194(7):886-897. doi: 10.1164/rccm.201512-2431OC.
• [8] Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.Nat Genet. 2008 Sep;40(9):1103-6. doi: 10.1038/ng.198.
• [9] CDH4 as a novel putative tumor suppressor gene epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma.Cancer Lett. 2011 Oct 1;309(1):54-61. doi: 10.1016/j.canlet.2011.05.016. Epub 2011 Jun 12.
• [10] Bioinformatics prediction and experimental validation of a novel microRNA: hsa-miR-B43 within human CDH4 gene with a potential metastasis-related function in breast cancer.J Cell Biochem. 2020 Feb;121(2):1307-1316. doi: 10.1002/jcb.29367. Epub 2019 Sep 6.
• [11] Study on expression of CDH4 in lung cancer.World J Surg Oncol. 2017 Jan 17;15(1):26. doi: 10.1186/s12957-016-1083-2.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] 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.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] 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.
• [21] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [26] 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.
• [27] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.