Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRK0M05)

• DOT Name: Protocadherin-17 (PCDH17)
• Synonyms: Protocadherin-68
• Gene Name: PCDH17
• Related Disease:
  Bladder transitional cell carcinoma
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Acute undifferentiated leukemia
  Bipolar disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Laryngeal squamous cell carcinoma
  Mood disorder
  Neoplasm
  Ovarian cancer
  Renal cell carcinoma
  Schizophrenia
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: PCD17_HUMAN
• PDB ID: 6VFT
• Pfam ID: PF00028 ; PF08266
• Sequence:
  MYLSICCCFLLWAPALTLKNLNYSVPEEQGAGTVIGNIGRDARLQPGLPPAERGGGGRSK
  SGSYRVLENSAPHLLDVDADSGLLYTKQRIDRESLCRHNAKCQLSLEVFANDKEICMIKV
  EIQDINDNAPSFSSDQIEMDISENAAPGTRFPLTSAHDPDAGENGLRTYLLTRDDHGLFG
  LDVKSRGDGTKFPELVIQKALDREQQNHHTLVLTALDGGEPPRSATVQINVKVIDSNDNS
  PVFEAPSYLVELPENAPLGTVVIDLNATDADEGPNGEVLYSFSSYVPDRVRELFSIDPKT
  GLIRVKGNLDYEENGMLEIDVQARDLGPNPIPAHCKVTVKLIDRNDNAPSIGFVSVRQGA
  LSEAAPPGTVIALVRVTDRDSGKNGQLQCRVLGGGGTGGGGGLGGPGGSVPFKLEENYDN
  FYTVVTDRPLDRETQDEYNVTIVARDGGSPPLNSTKSFAIKILDENDNPPRFTKGLYVLQ
  VHENNIPGEYLGSVLAQDPDLGQNGTVSYSILPSHIGDVSIYTYVSVNPTNGAIYALRSF
  NFEQTKAFEFKVLAKDSGAPAHLESNATVRVTVLDVNDNAPVIVLPTLQNDTAELQVPRN
  AGLGYLVSTVRALDSDFGESGRLTYEIVDGNDDHLFEIDPSSGEIRTLHPFWEDVTPVVE
  LVVKVTDHGKPTLSAVAKLIIRSVSGSLPEGVPRVNGEQHHWDMSLPLIVTLSTISIILL
  AAMITIAVKCKRENKEIRTYNCRIAEYSHPQLGGGKGKKKKINKNDIMLVQSEVEERNAM
  NVMNVVSSPSLATSPMYFDYQTRLPLSSPRSEVMYLKPASNNLTVPQGHAGCHTSFTGQG
  TNASETPATRMSIIQTDNFPAEPNYMGSRQQFVQSSSTFKDPERASLRDSGHGDSDQADS
  DQDTNKGSCCDMSVREALKMKTTSTKSQPLEQEPEECVNCTDECRVLGHSDRCWMPQFPA
  ANQAENADYRTNLFVPTVEANVETETYETVNPTGKKTFCTFGKDKREHTILIANVKPYLK
  AKRALSPLLQEVPSASSSPTKACIEPCTSTKGSLDGCEAKPGALAEASSQYLPTDSQYLS
  PSKQPRDPPFMASDQMARVFADVHSRASRDSSEMGAVLEQLDHPNRDLGRESVDAEEVVR
  EIDKLLQDCRGNDPVAVRK
• Function: Potential calcium-dependent cell-adhesion protein.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Posttranslational Modification	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Acute undifferentiated leukemia	DISJ4SSG	Strong	Altered Expression	[3]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Posttranslational Modification	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[11]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Altered Expression	[14]
Mood disorder	DISLVMWO	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Ovarian cancer	DISZJHAP	Strong	Posttranslational Modification	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[16]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[12]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[17]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Posttranslational Modification	[18]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[18]
Prostate cancer	DISF190Y	Limited	Posttranslational Modification	[19]
Prostate carcinoma	DISMJPLE	Limited	Posttranslational Modification	[19]

11 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 Protocadherin-17 (PCDH17).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protocadherin-17 (PCDH17).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protocadherin-17 (PCDH17).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protocadherin-17 (PCDH17).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protocadherin-17 (PCDH17).	[24]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Protocadherin-17 (PCDH17).	[26]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protocadherin-17 (PCDH17).	[27]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Protocadherin-17 (PCDH17).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protocadherin-17 (PCDH17).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protocadherin-17 (PCDH17).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protocadherin-17 (PCDH17).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Protocadherin-17 (PCDH17).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protocadherin-17 (PCDH17).	[29]

References

• [1] Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma.J Int Med Res. 2014 Apr;42(2):292-9. doi: 10.1177/0300060513504364. Epub 2014 Feb 24.
• [2] Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia.Pediatr Blood Cancer. 2017 Mar;64(3). doi: 10.1002/pbc.26259. Epub 2016 Sep 19.
• [3] Reduced protocadherin17 expression in leukemia stem cells: the clinical and biological effect in acute myeloid leukemia.J Transl Med. 2019 Mar 29;17(1):102. doi: 10.1186/s12967-019-1851-1.
• [4] The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.Mol Psychiatry. 2018 Feb;23(2):400-412. doi: 10.1038/mp.2016.231. Epub 2017 Jan 10.
• [5] p53/PCDH17/Beclin-1 Proteins as Prognostic Predictors for Urinary Bladder Cancer.J Cancer. 2019 Oct 15;10(25):6207-6216. doi: 10.7150/jca.37335. eCollection 2019.
• [6] Protocadherin 17 functions as a tumor suppressor suppressing Wnt/-catenin signaling and cell metastasis and is frequently methylated in breast cancer.Oncotarget. 2016 Aug 9;7(32):51720-51732. doi: 10.18632/oncotarget.10102.
• [7] Aberrant Promoter Methylation of PCDH17 (Protocadherin 17) in Serum and its Clinical Significance in Renal Cell Carcinoma.Med Sci Monit. 2017 Jul 8;23:3318-3323. doi: 10.12659/msm.902077.
• [8] PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death.Signal Transduct Target Ther. 2019 Nov 29;4:53. doi: 10.1038/s41392-019-0087-0. eCollection 2019.
• [9] LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy.Theranostics. 2019 Jun 10;9(15):4558-4566. doi: 10.7150/thno.31052. eCollection 2019.
• [10] Aberrant methylation of PCDH17 gene in high-grade serous ovarian carcinoma.Cancer Biomark. 2018;23(1):125-133. doi: 10.3233/CBM-181493.
• [11] Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma.Carcinogenesis. 2010 Jun;31(6):1027-36. doi: 10.1093/carcin/bgq053. Epub 2010 Mar 3.
• [12] PCDH17 gene promoter demethylation and cell cycle arrest by genistein in gastric cancer.Histol Histopathol. 2012 Feb;27(2):217-24. doi: 10.14670/HH-27.217.
• [13] Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma.Tumour Biol. 2016 Feb;37(2):2527-35. doi: 10.1007/s13277-015-3970-5. Epub 2015 Sep 19.
• [14] MiR-196b affects the progression and prognosis of human LSCC through targeting PCDH-17.Auris Nasus Larynx. 2019 Aug;46(4):583-592. doi: 10.1016/j.anl.2018.10.020. Epub 2018 Nov 16.
• [15] Protocadherin 17 is a tumor suppressor and is frequently methylated in nasopharyngeal carcinoma.Cancer Manag Res. 2019 Feb 18;11:1601-1613. doi: 10.2147/CMAR.S191102. eCollection 2019.
• [16] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [17] Recurrent transcriptional loss of the PCDH17 tumor suppressor in laryngeal squamous cell carcinoma is partially mediated by aberrant promoter DNA methylation.Mol Carcinog. 2018 Jul;57(7):878-885. doi: 10.1002/mc.22808. Epub 2018 Apr 6.
• [18] Aberrant promoter methylation reduced the expression of protocadherin 17 in nasopharyngeal cancer.Biochem Cell Biol. 2019 Aug;97(4):364-368. doi: 10.1139/bcb-2017-0343. Epub 2018 Aug 30.
• [19] Aberrant methylation of protocadherin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy.Med Sci Monit. 2014 Aug 5;20:1376-82. doi: 10.12659/MSM.891247.
• [20] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [25] 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.
• [26] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [27] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [28] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [29] 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.
• [30] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [31] 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.