Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19Z704)

• DOT Name: Dapper homolog 1 (DACT1)
• Synonyms: hDPR1; Dapper antagonist of catenin 1; Hepatocellular carcinoma novel gene 3 protein
• Gene Name: DACT1
• Related Disease:
  Nervous system disease
  Neural tube defects, susceptibility to
  Acute lymphocytic leukaemia
  Advanced cancer
  Carcinoma of esophagus
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Stomach cancer
  Transitional cell carcinoma
  Ear malformation
  Gastrointestinal stromal tumour
  leukaemia
  Leukemia
  Squamous cell carcinoma
  Townes-Brocks syndrome
  Asthma
  Hyperglycemia
  Neural tube defect
  Type-1/2 diabetes
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Nasopharyngeal carcinoma
  Non-insulin dependent diabetes
  Townes-Brocks syndrome 2
• UniProt ID: DACT1_HUMAN
• Pfam ID: PF15268
• Sequence:
  MKPSPAGTAKELEPPAPARGEQRTAEPEGRWREKGEADTERQRTRERQEATLAGLAELEY
  LRQRQELLVRGALRGAGGAGAAAPRAGELLGEAAQRSRLEEKFLEENILLLRKQLNCLRR
  RDAGLLNQLQELDKQISDLRLDVEKTSEEHLETDSRPSSGFYELSDGASGSLSNSSNSVF
  SECLSSCHSSTCFCSPLEATLSLSDGCPKSADLIGLLEYKEGHCEDQASGAVCRSLSTPQ
  FNSLDVIADVNPKYQCDLVSKNGNDVYRYPSPLHAVAVQSPMFLLCLTGNPLREEDRLGN
  HASDICGGSELDAVKTDSSLPSPSSLWSASHPSSSKKMDGYILSLVQKKTHPVRTNKPRT
  SVNADPTKGLLRNGSVCVRAPGGVSQGNSVNLKNSKQACLPSGGIPSLNNGTFSPPKQWS
  KESKAEQAESKRVPLPEGCPSGAASDLQSKHLPKTAKPASQEHARCSAIGTGESPKESAQ
  LSGASPKESPSRGPAPPQENKVVQPLKKMSQKNSLQGVPPATPPLLSTAFPVEERPALDF
  KSEGSSQSLEEAHLVKAQFIPGQQPSVRLHRGHRNMGVVKNSSLKHRGPALQGLENGLPT
  VREKTRAGSKKCRFPDDLDTNKKLKKASSKGRKSGGGPEAGVPGRPAGGGHRAGSRAHGH
  GREAVVAKPKHKRTDYRRWKSSAEISYEEALRRARRGRRENVGLYPAPVPLPYASPYAYV
  ASDSEYSAECESLFHSTVVDTSEDEQSNYTTNCFGDSESSVSEGEFVGESTTTSDSEESG
  GLIWSQFVQTLPIQTVTAPDLHNHPAKTFVKIKASHNLKKKILRFRSGSLKLMTTV
• Function: Involved in regulation of intracellular signaling pathways during development. Specifically thought to play a role in canonical and/or non-canonical Wnt signaling pathways through interaction with DSH (Dishevelled) family proteins. The activation/inhibition of Wnt signaling may depend on the phosphorylation status. Proposed to regulate the degradation of CTNNB1/beta-catenin, thereby modulating the transcriptional activation of target genes of the Wnt signaling pathway. Its function in stabilizing CTNNB1 may involve inhibition of GSK3B activity. Promotes the membrane localization of CTNNB1. The cytoplasmic form can induce DVL2 degradation via a lysosome-dependent mechanism; the function is inhibited by PKA-induced binding to 14-3-3 proteins, such as YWHAB. Seems to be involved in morphogenesis at the primitive streak by regulating VANGL2 and DVL2; the function seems to be independent of canonical Wnt signaling and rather involves the non-canonical Wnt/planar cell polarity (PCP) pathway. The nuclear form may prevent the formation of LEF1:CTNNB1 complex and recruit HDAC1 to LEF1 at target gene promoters to repress transcription thus antagonizing Wnt signaling. May be involved in positive regulation of fat cell differentiation. During neuronal differentiation may be involved in excitatory synapse organization, and dendrite formation and establishment of spines.
• Reactome Pathway: Degradation of DVL (R-HSA-4641258)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Neural tube defects, susceptibility to	DISHA84K	Definitive	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Gastric neoplasm	DISOKN4Y	Strong	Posttranslational Modification	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Posttranslational Modification	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Transitional cell carcinoma	DISWVVDR	Strong	Posttranslational Modification	[14]
Ear malformation	DISVJGPS	moderate	Biomarker	[15]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[16]
leukaemia	DISS7D1V	moderate	Biomarker	[12]
Leukemia	DISNAKFL	moderate	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[17]
Townes-Brocks syndrome	DISDR57E	Supportive	Autosomal dominant	[15]
Asthma	DISW9QNS	Disputed	Altered Expression	[18]
Hyperglycemia	DIS0BZB5	Disputed	Altered Expression	[19]
Neural tube defect	DIS5J95E	Disputed	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[19]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[20]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[20]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[20]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[21]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[22]
Townes-Brocks syndrome 2	DISQHOEP	Limited	Unknown	[15]

20 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 Dapper homolog 1 (DACT1).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dapper homolog 1 (DACT1).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dapper homolog 1 (DACT1).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dapper homolog 1 (DACT1).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dapper homolog 1 (DACT1).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dapper homolog 1 (DACT1).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Dapper homolog 1 (DACT1).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dapper homolog 1 (DACT1).	[30]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dapper homolog 1 (DACT1).	[31]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Dapper homolog 1 (DACT1).	[32]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Dapper homolog 1 (DACT1).	[30]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Dapper homolog 1 (DACT1).	[33]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Dapper homolog 1 (DACT1).	[34]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Dapper homolog 1 (DACT1).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dapper homolog 1 (DACT1).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dapper homolog 1 (DACT1).	[31]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Dapper homolog 1 (DACT1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dapper homolog 1 (DACT1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Dapper homolog 1 (DACT1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dapper homolog 1 (DACT1).	[39]

1 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 increases the methylation of Dapper homolog 1 (DACT1).	[36]

References

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• [2] Identification of novel rare mutations of DACT1 in human neural tube defects.Hum Mutat. 2012 Oct;33(10):1450-5. doi: 10.1002/humu.22121. Epub 2012 Jun 19.
• [3] Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia.Blood. 2007 Apr 15;109(8):3462-9. doi: 10.1182/blood-2006-09-047043. Epub 2006 Dec 5.
• [4] Oncogenic function of DACT1 in colon cancer through the regulation of -catenin.PLoS One. 2012;7(3):e34004. doi: 10.1371/journal.pone.0034004. Epub 2012 Mar 21.
• [5] Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma.J Biomed Sci. 2017 Jan 11;24(1):6. doi: 10.1186/s12929-016-0308-6.
• [6] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [7] An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER).Cardiovasc Drugs Ther. 2018 Apr;32(2):183-190. doi: 10.1007/s10557-018-6782-1.
• [8] DACT1 Overexpression in type I ovarian cancer inhibits malignant expansion and cis-platinum resistance by modulating canonical Wnt signalling and autophagy.Sci Rep. 2017 Aug 24;7(1):9285. doi: 10.1038/s41598-017-08249-7.
• [9] Cyclin G2 suppresses Wnt/-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1.J Exp Clin Cancer Res. 2018 Dec 14;37(1):317. doi: 10.1186/s13046-018-0973-2.
• [10] Dapper homolog 1 is a novel tumor suppressor in gastric cancer through inhibiting the nuclear factor-B signaling pathway.Mol Med. 2012 Dec 20;18(1):1402-11. doi: 10.2119/molmed.2012.00243.
• [11] MiR-324-3p promotes tumor growth through targeting DACT1 and activation of Wnt/-catenin pathway in hepatocellular carcinoma.Oncotarget. 2017 Aug 7;8(39):65687-65698. doi: 10.18632/oncotarget.20058. eCollection 2017 Sep 12.
• [12] DACT1 overexpression inhibits proliferation, enhances apoptosis, and increases daunorubicin chemosensitivity in KG-1 cells.Tumour Biol. 2017 Oct;39(10):1010428317711089. doi: 10.1177/1010428317711089.
• [13] Promise(s) of mesenchymal stem cells as an in vitro model system to depict pre-diabetic/diabetic milieu in WNIN/GR-Ob mutant rats.PLoS One. 2012;7(10):e48061. doi: 10.1371/journal.pone.0048061. Epub 2012 Oct 29.
• [14] Relationships among MTHFR a1298c gene polymorphisms and methylation status of Dact1 gene in transitional cell carcinomas.Asian Pac J Cancer Prev. 2012;13(10):5069-74. doi: 10.7314/apjcp.2012.13.10.5069.
• [15] Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome. Hum Mutat. 2017 Apr;38(4):373-377. doi: 10.1002/humu.23171. Epub 2017 Feb 2.
• [16] A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number.Lab Invest. 2010 Sep;90(9):1285-94. doi: 10.1038/labinvest.2010.110. Epub 2010 Jun 14.
• [17] Expression and epigenetic regulation of DACT1 and DACT2 in oral squamous cell carcinoma.Cancer Biomark. 2015;15(1):11-7. doi: 10.3233/CBM-140436.
• [18] Expression of DACT1 in children with asthma and its regulation mechanism.Exp Ther Med. 2018 Mar;15(3):2674-2680. doi: 10.3892/etm.2018.5706. Epub 2018 Jan 5.
• [19] Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling.Mol Cell Endocrinol. 2017 May 15;447:106-115. doi: 10.1016/j.mce.2017.02.028. Epub 2017 Feb 24.
• [20] DACT1, an antagonist to Wnt/-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer.Breast Cancer Res. 2013 Mar 12;15(2):R23. doi: 10.1186/bcr3399.
• [21] Effects of DACT1 methylation status on invasion and metastasis of nasopharyngeal carcinoma.Biol Res. 2019 Jun 10;52(1):31. doi: 10.1186/s40659-019-0238-3.
• [22] MicroRNA-125b-5p improves pancreatic -cell function through inhibiting JNK signaling pathway by targeting DACT1 in mice with type 2 diabetes mellitus.Life Sci. 2019 May 1;224:67-75. doi: 10.1016/j.lfs.2019.01.031. Epub 2019 Jan 23.
• [23] 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.
• [24] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [25] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [30] 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.
• [31] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [32] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [33] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [34] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [35] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [36] 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.
• [37] 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.
• [38] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [39] 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.