Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3SRZ6)

• DOT Name: Cadherin-8 (CDH8)
• Gene Name: CDH8
• Related Disease:
  Alcohol dependence
  Autism
  Autism spectrum disorder
  Autosomal dominant polycystic kidney disease
  Clear cell renal carcinoma
  Major depressive disorder
  Mood disorder
  Neoplasm
  Parkinson disease
  Renal cell carcinoma
  Hepatocellular carcinoma
• UniProt ID: CADH8_HUMAN
• Pfam ID: PF01049 ; PF00028
• Sequence:
  MPERLAEMLLDLWTPLIILWITLPPCIYMAPMNQSQVLMSGSPLELNSLGEEQRILNRSK
  RGWVWNQMFVLEEFSGPEPILVGRLHTDLDPGSKKIKYILSGDGAGTIFQINDVTGDIHA
  IKRLDREEKAEYTLTAQAVDWETSKPLEPPSEFIIKVQDINDNAPEFLNGPYHATVPEMS
  ILGTSVTNVTATDADDPVYGNSAKLVYSILEGQPYFSIEPETAIIKTALPNMDREAKEEY
  LVVIQAKDMGGHSGGLSGTTTLTVTLTDVNDNPPKFAQSLYHFSVPEDVVLGTAIGRVKA
  NDQDIGENAQSSYDIIDGDGTALFEITSDAQAQDGIIRLRKPLDFETKKSYTLKVEAANV
  HIDPRFSGRGPFKDTATVKIVVEDADEPPVFSSPTYLLEVHENAALNSVIGQVTARDPDI
  TSSPIRFSIDRHTDLERQFNINADDGKITLATPLDRELSVWHNITIIATEIRNHSQISRV
  PVAIKVLDVNDNAPEFASEYEAFLCENGKPGQVIQTVSAMDKDDPKNGHYFLYSLLPEMV
  NNPNFTIKKNEDNSLSILAKHNGFNRQKQEVYLLPIIISDSGNPPLSSTSTLTIRVCGCS
  NDGVVQSCNVEAYVLPIGLSMGALIAILACIILLLVIVVLFVTLRRHKNEPLIIKDDEDV
  RENIIRYDDEGGGEEDTEAFDIATLQNPDGINGFLPRKDIKPDLQFMPRQGLAPVPNGVD
  VDEFINVRLHEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESTTSDSDQNFDYLSDWG
  PRFKRLGELYSVGESDKET
• 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.
• Tissue Specificity: Mainly expressed in brain. Found in certain nerve cell lines, such as retinoblasts, glioma cells and neuroblasts.
• Reactome Pathway:
  CDH11 homotypic and heterotypic interactions (R-HSA-9833576)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[7]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]

13 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-8 (CDH8).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cadherin-8 (CDH8).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cadherin-8 (CDH8).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cadherin-8 (CDH8).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cadherin-8 (CDH8).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-8 (CDH8).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cadherin-8 (CDH8).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Cadherin-8 (CDH8).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cadherin-8 (CDH8).	[17]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Cadherin-8 (CDH8).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cadherin-8 (CDH8).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cadherin-8 (CDH8).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Cadherin-8 (CDH8).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cadherin-8 (CDH8).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cadherin-8 (CDH8).	[21]

References

• [1] Cadherins and neuropsychiatric disorders.Brain Res. 2012 Aug 27;1470:130-44. doi: 10.1016/j.brainres.2012.06.020. Epub 2012 Jul 2.
• [2] Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability.J Med Genet. 2011 Jan;48(1):48-54. doi: 10.1136/jmg.2010.079426. Epub 2010 Oct 23.
• [3] Identification of candidate intergenic risk loci in autism spectrum disorder.BMC Genomics. 2013 Jul 24;14:499. doi: 10.1186/1471-2164-14-499.
• [4] Ectopic expression of cadherin 8 is sufficient to cause cyst formation in a novel 3D collagen matrix renal tubule culture.Am J Physiol Cell Physiol. 2011 Jul;301(1):C99-C105. doi: 10.1152/ajpcell.00151.2010. Epub 2011 Mar 9.
• [5] Expression of cadherin-8 in renal cell carcinoma and fetal kidney.Int J Cancer. 2002 Oct 1;101(4):327-34. doi: 10.1002/ijc.10623.
• [6] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [7] Molecular Pap smear: HPV genotype and DNA methylation of ADCY8, CDH8, and ZNF582 as an integrated biomarker for high-grade cervical cytology.Clin Epigenetics. 2016 Sep 13;8(1):96. doi: 10.1186/s13148-016-0263-9. eCollection 2016.
• [8] Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population.BMC Med Genet. 2011 Aug 3;12:104. doi: 10.1186/1471-2350-12-104.
• [9] Meta-analysis of possible role of cadherin gene methylation in evolution and prognosis of hepatocellular carcinoma with a PRISMA guideline.Medicine (Baltimore). 2017 Apr;96(16):e6650. doi: 10.1097/MD.0000000000006650.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.