Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81DIOD)

• DOT Name: FXYD domain-containing ion transport regulator 5 (FXYD5)
• Synonyms: Dysadherin
• Gene Name: FXYD5
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cystic fibrosis
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm of testis
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic tumour
  Pneumonia
  Pneumonitis
  Seminoma
  Squamous cell carcinoma
  Synovial sarcoma
  Gastrointestinal stromal tumour
  Graft-versus-host disease
  Myelofibrosis
  Non-insulin dependent diabetes
  Peripheral arterial disease
  Primary myelofibrosis
  Gastric neoplasm
  Malignant rhabdoid tumour
  Stroke
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
• UniProt ID: FXYD5_HUMAN
• Pfam ID: PF02038
• Sequence:
  MSPSGRLCLLTIVGLILPTRGQTLKDTTSSSSADSTIMDIQVPTRAPDAVYTELQPTSPT
  PTWPADETPQPQTQTQQLEGTDGPLVTDPETHKSTKAAHPTDDTTTLSERPSPSTDVQTD
  PQTLKPSGFHEDDPFFYDEHTLRKRGLLVAAVLFITGIIILTSGKCRQLSRLCRNRCR
• Function: Involved in down-regulation of E-cadherin which results in reduced cell adhesion. Promotes metastasis.

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[9]
Neoplasm of testis	DISK4XHT	Strong	Altered Expression	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[11]
Pneumonia	DIS8EF3M	Strong	Biomarker	[12]
Pneumonitis	DIS88E0K	Strong	Biomarker	[12]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[13]
Synovial sarcoma	DISEZJS7	Strong	Altered Expression	[14]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[15]
Graft-versus-host disease	DIS0QADF	moderate	Genetic Variation	[16]
Myelofibrosis	DISIMP21	moderate	Biomarker	[17]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Biomarker	[18]
Peripheral arterial disease	DIS78WFB	moderate	Biomarker	[18]
Primary myelofibrosis	DIS6L0CN	moderate	Biomarker	[17]
Gastric neoplasm	DISOKN4Y	Disputed	Biomarker	[19]
Malignant rhabdoid tumour	DIS46HZU	Limited	Altered Expression	[20]
Stroke	DISX6UHX	Limited	Biomarker	[21]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[22]
Thyroid gland carcinoma	DISMNGZ0	Limited	Altered Expression	[22]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[22]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[29]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[31]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[29]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[32]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[32]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[36]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of FXYD domain-containing ion transport regulator 5 (FXYD5).	[37]

References

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• [2] A FXYD5/TGF?SMAD positive feedback loop drives epithelialtomesenchymal transition and promotes tumor growth and metastasis in ovarian cancer.Int J Oncol. 2020 Jan;56(1):301-314. doi: 10.3892/ijo.2019.4911. Epub 2019 Nov 13.
• [3] Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma.J Hematol Oncol. 2017 Jun 12;10(1):117. doi: 10.1186/s13045-017-0487-y.
• [4] FXYD5 (dysadherin) may mediate metastatic progression through regulation of the -Na(+)-K(+)-ATPase subunit in the 4T1 mouse breast cancer model.Am J Physiol Cell Physiol. 2017 Jul 1;313(1):C108-C117. doi: 10.1152/ajpcell.00206.2016. Epub 2017 May 17.
• [5] In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin.Br J Cancer. 2007 May 7;96(9):1404-8. doi: 10.1038/sj.bjc.6603743. Epub 2007 Apr 17.
• [6] Let-7a down-regulation plays a role in thyroid neoplasias of follicular histotype affecting cell adhesion and migration through its ability to target the FXYD5 (Dysadherin) gene.J Clin Endocrinol Metab. 2012 Nov;97(11):E2168-78. doi: 10.1210/jc.2012-1929. Epub 2012 Sep 10.
• [7] Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells.J Hepatol. 2011 Jan;54(1):122-31. doi: 10.1016/j.jhep.2010.06.026. Epub 2010 Aug 26.
• [8] FXYD5 modulates Na+ absorption and is increased in cystic fibrosis airway epithelia.Am J Physiol Lung Cell Mol Physiol. 2008 Apr;294(4):L654-64. doi: 10.1152/ajplung.00430.2007. Epub 2008 Feb 8.
• [9] Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients.Cancer. 2005 Apr 15;103(8):1693-700. doi: 10.1002/cncr.20984.
• [10] Involvement of dysadherin and E-cadherin in the development of testicular tumours.Br J Cancer. 2005 Dec 12;93(12):1382-7. doi: 10.1038/sj.bjc.6602880.
• [11] Dysadherin expression facilitates cell motility and metastatic potential of human pancreatic cancer cells.Cancer Res. 2004 Oct 1;64(19):6989-95. doi: 10.1158/0008-5472.CAN-04-1166.
• [12] FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury.Front Immunol. 2017 Jun 1;8:623. doi: 10.3389/fimmu.2017.00623. eCollection 2017.
• [13] Prognostic significance of dysadherin expression in esophageal squamous cell carcinoma.Oncology. 2004;67(1):73-80. doi: 10.1159/000080289.
• [14] Dysadherin expression as a significant prognostic factor and as a determinant of histologic features in synovial sarcoma: special reference to its inverse relationship with E-cadherin expression.Am J Surg Pathol. 2007 Jan;31(1):85-94. doi: 10.1097/01.pas.0000213413.33558.85.
• [15] Dysadherin expression in gastrointestinal stromal tumors (GISTs).Pathol Res Pract. 2009;205(7):445-50. doi: 10.1016/j.prp.2008.12.020. Epub 2009 Feb 12.
• [16] Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience.Bone Marrow Transplant. 2010 Mar;45(3):534-42. doi: 10.1038/bmt.2009.180. Epub 2009 Aug 10.
• [17] Allogeneic hematopoietic stem cell transplantation with fludarabine, busulfan, and thiotepa conditioning is associated with favorable outcomes in myelofibrosis.Bone Marrow Transplant. 2020 Jan;55(1):147-156. doi: 10.1038/s41409-019-0653-7. Epub 2019 Aug 28.
• [18] Efficacy of Long-Term Remote Ischemic Conditioning on Vascular and Neuronal Function in Type 2 Diabetes Patients With Peripheral Arterial Disease.J Am Heart Assoc. 2019 Jul 2;8(13):e011779. doi: 10.1161/JAHA.118.011779. Epub 2019 Jun 19.
• [19] Clinical significance of dysadherin expression in gastric cancer patients.Clin Cancer Res. 2004 Apr 15;10(8):2818-23. doi: 10.1158/1078-0432.ccr-0633-03.
• [20] Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor.Mod Pathol. 2006 Jun;19(6):820-31. doi: 10.1038/modpathol.3800599.
• [21] Remote Ischemic Conditioning After Stroke Trial 2: A Phase IIb Randomized Controlled Trial in Hyperacute Stroke.J Am Heart Assoc. 2019 Dec 3;8(23):e013572. doi: 10.1161/JAHA.119.013572. Epub 2019 Nov 21.
• [22] Dysadherin specific drug conjugates for the treatment of thyroid cancers with aggressive phenotypes.Oncotarget. 2017 Apr 11;8(15):24457-24468. doi: 10.18632/oncotarget.14904.
• [23] 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.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [26] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [30] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [31] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [32] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [33] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [34] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [35] 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.
• [36] 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.
• [37] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.