Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNLCC0K)

• DOT Name: Dapper homolog 2 (DACT2)
• Synonyms: Dapper antagonist of catenin 2
• Gene Name: DACT2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric adenocarcinoma
  Glioma
  Hepatocellular carcinoma
  Hypothyroidism
  Lung cancer
  Lung carcinoma
  Nasopharyngeal carcinoma
  Neoplasm
  Neoplasm of esophagus
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Carcinoma
  Squamous cell carcinoma
  Asthma
  Liver cancer
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
• UniProt ID: DACT2_HUMAN
• Pfam ID: PF15268
• Sequence:
  MWTPGGPPGSAGWDRRRLGARLRAAFAGLQELQGLRATQQERVRGALALQPPPAPAAPCG
  PHGLHGPEQQLEAALAALQEQLSRLRQQDIGLKTHLDQLDLQISKLQLDVGTASGEALDS
  DSRPSSGFYEMSDGGSCSLSTSCASVCSDHISPSLGSLLPVAQAHKARPSMGDWRPRSVD
  ETTVPAWRPQATEEGARPPGSVEDAGQPWGTFWPRPVSTGDLDRALPADTGLQKASADAE
  LLGLLCQGVDIPLHVPDPKYRQDLVSQGGREVYPYPSPLHAVALQSPLFVLTKETPQRGG
  PSFPRESPRGPAGLNTIQTGPVLEAGPARARAYIDRLLHLWGRETPAKGSEGEQGPLRHA
  ASPSPQRQGGWSTDGGGRLLVFAPGREDEGGPAQSRGAGRGGPQQQGYMPLEGPQQSGSL
  PEEGSKPSNSCVLRETMVQASPSSKAQQTPSAQDYGRGNIISPSRMLDKSPSPASGHFAH
  PSFAASLKMGPPKSKAEKIKRSPMDKVLRFARQPLLLLDRPEGAHAAPQPSLEWDPAHWP
  TGRGGLQRRPALAWEAPGRSCSESTLYPMPVLVPLAVAPQESHRTSAQALFPFEASLLTS
  VARRKHRRWQSTVEISARARLASCPESNLGPPRPVARRAGGPLARGRPSLVRQDAYTRSD
  SEPSKHSAECDPRFPSVIPETSEGESSDHTTNRFGDRESSSSDEEGGAQSRDCDLALGYV
  AAGHAELAWTQEAPVSSGPLLSPVPKLCRIKASKALKKKIRRFQPTALKVMTMV
• Function: Involved in regulation of intracellular signaling pathways during development. Negatively regulates the Nodal signaling pathway, possibly by promoting the lysosomal degradation of Nodal receptors, such as TGFBR1. May be involved in control of the morphogenetic behavior of kidney ureteric bud cells by keeping cells epithelial and restraining their mesenchymal character. May play an inhibitory role in the re-epithelialization of skin wounds by attenuating TGF-beta signaling.

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[1]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[9]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[9]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[9]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[1]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[12]
Thyroid cancer	DIS3VLDH	Strong	Posttranslational Modification	[13]
Thyroid gland carcinoma	DISMNGZ0	Strong	Posttranslational Modification	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Posttranslational Modification	[9]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[9]
Carcinoma	DISH9F1N	moderate	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[15]
Asthma	DISW9QNS	Disputed	Altered Expression	[16]
Liver cancer	DISDE4BI	Disputed	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[12]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dapper homolog 2 (DACT2).	[19]

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 2 (DACT2).	[20]

References

• [1] Association between promoter hypermethylation of the DACT2 gene and tumor stages in breast cancer.J BUON. 2018 Mar-Apr;23(2):361-365.
• [2] DACT2 silencing by promoter CpG methylation disrupts its regulation of epithelial-to-mesenchymal transition and cytoskeleton reorganization in breast cancer cells.Oncotarget. 2016 Oct 25;7(43):70924-70935. doi: 10.18632/oncotarget.12341.
• [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] DACT2 is a functional tumor suppressor through inhibiting Wnt/-catenin pathway and associated with poor survival in colon cancer.Oncogene. 2015 May 14;34(20):2575-85. doi: 10.1038/onc.2014.201. Epub 2014 Jul 14.
• [5] DACT2 Epigenetic Stimulator Exerts Dual Efficacy for Colorectal Cancer Prevention and Treatment.Pharmacol Res. 2018 Mar;129:318-328. doi: 10.1016/j.phrs.2017.11.032. Epub 2017 Dec 1.
• [6] Flat adenoma-carcinoma sequence with high-malignancy potential as demonstrated by CD10 and beta-catenin expression: a different pathway from the polypoid adenoma-carcinoma sequence.Histopathology. 2008 Apr;52(5):569-77. doi: 10.1111/j.1365-2559.2008.02996.x.
• [7] MicroRNA-214 promotes the proliferation, migration and invasion of gastric cancer MKN28 cells by suppressing the expression of Dact2.Exp Ther Med. 2018 Dec;16(6):4909-4917. doi: 10.3892/etm.2018.6771. Epub 2018 Sep 19.
• [8] Upregulation of DACT2 suppresses proliferation and enhances apoptosis of glioma cell via inactivation of YAP signaling pathway.Cell Death Dis. 2017 Aug 10;8(8):e2981. doi: 10.1038/cddis.2017.385.
• [9] Methylation of DACT2 promotes papillary thyroid cancer metastasis by activating Wnt signaling.PLoS One. 2014 Nov 6;9(11):e112336. doi: 10.1371/journal.pone.0112336. eCollection 2014.
• [10] Linkage and association analysis of hyperthyrotropinaemia in an Alpine population reveal two novel loci on chromosomes 3q28-29 and 6q26-27.J Med Genet. 2011 Aug;48(8):549-56. doi: 10.1136/jmg.2010.088583. Epub 2011 Jun 20.
• [11] The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via -catenin/Cdc25c signaling and G2/M arrest.Clin Epigenetics. 2018 Feb 27;10(1):26. doi: 10.1186/s13148-018-0459-2.
• [12] Downregulation of DACT-2 by Promoter Methylation and its Clinicopathological Significance in Prostate Cancer.J Cancer. 2019 Apr 20;10(7):1755-1763. doi: 10.7150/jca.28577. eCollection 2019.
• [13] Methylation of DACT2 accelerates esophageal cancer development by activating Wnt signaling.Oncotarget. 2016 Apr 5;7(14):17957-69. doi: 10.18632/oncotarget.7647.
• [14] Prognostic significance of the methylation of Wnt pathway antagonists-CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling-ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas.Clin Oral Investig. 2017 Jun;21(5):1777-1788. doi: 10.1007/s00784-016-1946-5. Epub 2016 Aug 23.
• [15] 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.
• [16] 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.
• [17] Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.PLoS One. 2014 Jul 24;9(7):e102579. doi: 10.1371/journal.pone.0102579. eCollection 2014.
• [18] Reduced expression of DACT2 promotes hepatocellular carcinoma progression: involvement of methylation-mediated gene silencing.World J Surg Oncol. 2013 Mar 7;11:57. doi: 10.1186/1477-7819-11-57.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.