Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDDOQM2)

• DOT Name: Protocadherin-8 (PCDH8)
• Synonyms: Arcadlin
• Gene Name: PCDH8
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Hypopharyngeal carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Schizophrenia
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
  Isolated congenital microcephaly
  Nasopharyngeal carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Prostate cancer
  Type-1/2 diabetes
• UniProt ID: PCDH8_HUMAN
• PDB ID: 6VFV
• Pfam ID: PF00028 ; PF08266
• Sequence:
  MSPVRRWGSPCLFPLQLFSLCWVLSVAQSKTVRYSTFEEDAPGTVIGTLAEDLHMKVSGD
  TSFRLMKQFNSSLLRVREGDGQLTVGDAGLDRERLCGQAPQCVLAFDVVSFSQEQFRLVH
  VEVEVRDVNDHAPRFPRAQIPVEVSEGAAVGTRIPLEVPVDEDVGANGLQTVRLAEPHSP
  FRVELQTRADGAQCADLVLLQELDRESQAAYSLELVAQDGGRPPRSATAALSVRVLDAND
  HSPAFPQGAVAEVELAEDAPVGSLLLDLDAADPDEGPNGDVVFAFGARTPPEARRLFRLD
  PRSGRLTLAGPVDYERQDTYELDVRAQDRGPGPRAATCKVIVRIRDVNDNAPDIAITPLA
  APGAPATSPFAAAAAAAALGGADASSPAGAGTPEAGATSLVPEGAARESLVALVSTSDRD
  SGANGQVRCALYGHEHFRLQPAYAGSYLVVTAASLDRERIAEYNLTLVAEDRGAPPLRTV
  RPYTVRVGDENDNAPLFTRPVYEVSVRENNPPGAYLATVAARDRDLGRNGQVTYRLLEAE
  VGRAGGAVSTYVSVDPATGAIYALRSFDYETLRQLDVRIQASDGGSPQLSSSALVQVRVL
  DQNDHAPVLVHPAPANGSLEVAVPGRTAKDTVVARVQARDADEGANGELAFELQQQEPRE
  AFAIGRRTGEILLTGDLSQEPPGRVFRALLVISDGGRPPLTTTATVSFVVTAGGGRGPAA
  PASAGSPERSRPPGSRLGVSGSVLQWDTPLIVIIVLAGSCTLLLAAIIAIATTCNRRKKE
  VRKGGALREERPGAAGGGASAPGSPEEAARGAGPRPNMFDVLTFPGTGKAPFGSPAADAP
  PPAVAAAEVPGSEGGSATGESACHFEGQQRLRGAHAEPYGASPGFGKEPAPPVAVWKGHS
  FNTISGREAEKFSGKDSGKGDSDFNDSDSDISGDALKKDLINHMQSGLWACTAECKILGH
  SDRCWSPSCSGPNAHPSPHPPAQMSTFCKSTSLPRDPLRRDNYYQAQLPKTVGLQSVYEK
  VLHRDYDRTVTLLSPPRPGRLPDLQEIGVPLYQSPPGRYLSPKKGANENV
• Function: Calcium-dependent cell-adhesion protein. May play a role in activity-induced synaptic reorganization underlying long term memory. Could be involved in CDH2 internalization through TAOK2/p38 MAPK pathway. In hippocampal neurons, may play a role in the down-regulation of dendritic spines, maybe through its action on CDH2 endocytosis.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[1]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[11]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[12]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	Disputed	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[14]
Prostate cancer	DISF190Y	Limited	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

2 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 Protocadherin-8 (PCDH8).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protocadherin-8 (PCDH8).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protocadherin-8 (PCDH8).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protocadherin-8 (PCDH8).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protocadherin-8 (PCDH8).	[19]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protocadherin-8 (PCDH8).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protocadherin-8 (PCDH8).	[21]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Protocadherin-8 (PCDH8).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protocadherin-8 (PCDH8).	[21]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protocadherin-8 (PCDH8).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protocadherin-8 (PCDH8).	[21]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Protocadherin-8 (PCDH8).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protocadherin-8 (PCDH8).	[26]

References

• [1] Protocadherin-8 promotes invasion and metastasis via laminin subunit 2 in gastric cancer.Cancer Sci. 2018 Mar;109(3):732-740. doi: 10.1111/cas.13502. Epub 2018 Feb 20.
• [2] Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo.J Biol Chem. 2007 Oct 26;282(43):31460-8. doi: 10.1074/jbc.M704267200. Epub 2007 Aug 28.
• [3] Association between protocadherin 8 promoter hypermethylation and the pathological status of prostate cancer.Oncol Lett. 2017 Aug;14(2):1657-1664. doi: 10.3892/ol.2017.6282. Epub 2017 May 31.
• [4] Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer.Oncol Rep. 2012 Nov;28(5):1785-91. doi: 10.3892/or.2012.1997. Epub 2012 Aug 30.
• [5] Low Expression of Protocadherin-8 Promotes the Progression of Ovarian Cancer.Int J Gynecol Cancer. 2018 Feb;28(2):346-354. doi: 10.1097/IGC.0000000000001169.
• [6] PCDH8 inhibits glioma cell proliferation by negatively regulating the AKT/GSK3/-catenin signaling pathway.Oncol Lett. 2017 Sep;14(3):3357-3362. doi: 10.3892/ol.2017.6629. Epub 2017 Jul 20.
• [7] Expression of protocadherin8: Function as a tumor suppressor in hypopharyngeal carcinoma.Cancer Biomark. 2018;22(3):495-502. doi: 10.3233/CBM-171137.
• [8] Aberrant Promoter Methylation of Protocadherin8 (PCDH8) in Serum is a Potential Prognostic Marker for Low Gleason Score Prostate Cancer.Med Sci Monit. 2017 Oct 13;23:4895-4900. doi: 10.12659/msm.904366.
• [9] Microarray comparison of prostate tumor gene expression in African-American and Caucasian American males: a pilot project study.Infect Agent Cancer. 2009 Feb 10;4 Suppl 1(Suppl 1):S3. doi: 10.1186/1750-9378-4-S1-S3.
• [10] Screening the human protocadherin 8 (PCDH8) gene in schizophrenia.Genes Brain Behav. 2002 Aug;1(3):187-91. doi: 10.1034/j.1601-183x.2002.10307.x.
• [11] miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis.Cancer Res. 2016 Jul 15;76(14):4293-304. doi: 10.1158/0008-5472.CAN-15-3073. Epub 2016 May 31.
• [12] Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions.Eur J Hum Genet. 2011 Sep;19(9):947-58. doi: 10.1038/ejhg.2011.58. Epub 2011 Apr 20.
• [13] Protocadherin8 is a functional tumor suppressor frequently inactivated by promoter methylation in nasopharyngeal carcinoma.Eur J Cancer Prev. 2012 Nov;21(6):569-75. doi: 10.1097/CEJ.0b013e328350b097.
• [14] Defective metabolism of oxidized phospholipid by HDL from people with type 2 diabetes.Diabetes. 2006 Nov;55(11):3099-103. doi: 10.2337/db06-0723.
• [15] Prevalence of virulence factors and phylogenetic characterization of uropathogenic Escherichia coli causing urinary tract infection in patients with and without diabetes mellitus.Trans R Soc Trop Med Hyg. 2015 Dec;109(12):769-74. doi: 10.1093/trstmh/trv086. Epub 2015 Nov 12.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] 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.
• [22] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [23] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [24] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [25] 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.
• [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.