Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSNQ55G)

• DOT Name: Dapper homolog 3 (DACT3)
• Synonyms: Antagonist of beta-catenin Dapper homolog 3; Arginine-rich region 1 protein; Dapper antagonist of catenin 3
• Gene Name: DACT3
• Related Disease:
  Advanced cancer
  Carcinoma
  Carcinoma of esophagus
  Colorectal carcinoma
  Colorectal neoplasm
  Esophageal cancer
  Neoplasm of esophagus
  Polycystic ovarian syndrome
  Asthma
• UniProt ID: DACT3_HUMAN
• Pfam ID: PF15268
• Sequence:
  MIRAFSFPVSPERGRLRGWLEGSLAGLCELHWLRERQEYRVQQALRLAQPGMGGAEAEDE
  EDADEDEDAAAARRAAAALEEQLEALPGLVWDLGQQLGDLSLESGGLEQESGRSSGFYED
  PSSTGGPDSPPSTFCGDSGFSGSSSYGRLGPSEPRGIYASERPKSLGDASPSAPEVVGAR
  AAVPRSFSAPYPTAGGSAGPEACSSAERRARAGPFLTPSPLHAVAMRSPRPCGRPPTDSP
  DAGGAGRPLDGYISALLRRRRRRGAGQPRTSPGGADGGPRRQNSVRQRPPDASPSPGSAR
  PAREPSLERVGGHPTSPAALSRAWASSWESEAAPEPAAPPAAPSPPDSPAEGRLVKAQYI
  PGAQAATRGLPGRAARRKPPPLTRGRSVEQSPPRERPRAAGRRGRMAEASGRRGSPRARK
  ASRSQSETSLLGRASAVPSGPPKYPTAEREEPRPPRPRRGPAPTLAAQAAGSCRRWRSTA
  EIDAADGRRVRPRAPAARVPGPGPSPSAPQRRLLYGCAGSDSECSAGRLGPLGRRGPAGG
  VGGGYGESESSASEGESPAFSSASSDSDGSGGLVWPQQLVAATAASGGGAGAGAPAGPAK
  VFVKIKASHALKKKILRFRSGSLKVMTTV
• Function: May be 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.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Colorectal neoplasm	DISR1UCN	Strong	Posttranslational Modification	[4]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[5]
Asthma	DISW9QNS	Disputed	Altered Expression	[6]

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 Dapper homolog 3 (DACT3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dapper homolog 3 (DACT3).	[18]

16 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 Dapper homolog 3 (DACT3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dapper homolog 3 (DACT3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dapper homolog 3 (DACT3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dapper homolog 3 (DACT3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dapper homolog 3 (DACT3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Dapper homolog 3 (DACT3).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Dapper homolog 3 (DACT3).	[4]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Dapper homolog 3 (DACT3).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Dapper homolog 3 (DACT3).	[16]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Dapper homolog 3 (DACT3).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dapper homolog 3 (DACT3).	[19]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Dapper homolog 3 (DACT3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dapper homolog 3 (DACT3).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dapper homolog 3 (DACT3).	[4]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Dapper homolog 3 (DACT3).	[21]
DZNep	DM0JXBK	Investigative	DZNep affects the expression of Dapper homolog 3 (DACT3).	[4]

References

• [1] MiRNA-638 promotes autophagy and malignant phenotypes of cancer cells via directly suppressing DACT3.Cancer Lett. 2017 Apr 1;390:126-136. doi: 10.1016/j.canlet.2017.01.009. Epub 2017 Jan 18.
• [2] Anterior tongue cancer with no history of tobacco and alcohol use may be a distinct molecular and clinical entity.J Oral Pathol Med. 2014 Sep;43(8):593-9. doi: 10.1111/jop.12175. Epub 2014 May 9.
• [3] 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.
• [4] DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008 Jun;13(6):529-41. doi: 10.1016/j.ccr.2008.04.019.
• [5] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008 Jun;13(6):529-41. doi: 10.1016/j.ccr.2008.04.019.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [18] 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.
• [19] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [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] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.