Details of Drug Off-Target (DOT)

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

• DOT Name: Dachshund homolog 1 (DACH1)
• Synonyms: Dach1
• Gene Name: DACH1
• Related Disease:
  Chronic renal failure
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Carcinoma of esophagus
  Cardiovascular disease
  Cholelithiasis
  Clear cell renal carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Esophageal cancer
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Malignant peripheral nerve sheath tumor
  Myeloid leukaemia
  Neoplasm
  Neoplasm of esophagus
  Neurofibromatosis type 1
  Obesity
  Oral cancer
  Oral cavity carcinoma
  Pancreatic cancer
  Postaxial polydactyly type A
  Prediabetes syndrome
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Renal dysplasia
  Stomach cancer
  Glioma
  Invasive breast carcinoma
  Laryngeal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Small-cell lung cancer
  Advanced cancer
  Chronic kidney disease
  Male breast carcinoma
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
• UniProt ID: DACH1_HUMAN
• PDB ID: 1L8R
• Pfam ID: PF02437
• Sequence:
  MAVPAALIPPTQLVPPQPPISTSASSSGTTTSTSSATSSPAPSIGPPASSGPTLFRPEPI
  ASAAAAAATVTSTGGGGGGGGSGGGGGSSGNGGGGGGGGGGSNCNPNLAAASNGSGGGGG
  GISAGGGVASSTPINASTGSSSSSSSSSSSSSSSSSSSSSSSSCGPLPGKPVYSTPSPVE
  NTPQNNECKMVDLRGAKVASFTVEGCELICLPQAFDLFLKHLVGGLHTVYTKLKRLEITP
  VVCNVEQVRILRGLGAIQPGVNRCKLISRKDFETLYNDCTNASSRPGRPPKRTQSVTSPE
  NSHIMPHSVPGLMSPGIIPPTGLTAAAAAAAAATNAAIAEAMKVKKIKLEAMSNYHASNN
  QHGADSENGDMNSSVGSSDGSWDKETLPSSPSQGPQASITHPRMPGARSLPLSHPLNHLQ
  QSHLLPNGLELPFMMMPHPLIPVSLPPASVTMAMSQMNHLSTIANMAAAAQVQSPPSRVE
  TSVIKERVPDSPSPAPSLEEGRRPGSHPSSHRSSSVSSSPARTESSSDRIPVHQNGLSMN
  QMLMGLSPNVLPGPKEGDLAGHDMGHESKRMHIEKDETPLSTPTARDSLDKLSLTGHGQP
  LPPGFPSPFLFPDGLSSIETLLTNIQGLLKVAIDNARAQEKQVQLEKTELKMDFLREREL
  RETLEKQLAMEQKNRAIVQKRLKKEKKAKRKLQEALEFETKRREQAEQTLKQAASTDSLR
  VLNDSLTPEIEADRSGGRTDAERTIQDGRLYLKTTVMY
• Function: Transcription factor that is involved in regulation of organogenesis. Seems to be a regulator of SIX1, SIX6 and probably SIX5. Corepression of precursor cell proliferation in myoblasts by SIX1 is switched to coactivation through recruitment of EYA3 to the SIX1-DACH1 complex. Transcriptional activation seems also to involve association of CREBBP. Seems to act as a corepressor of SIX6 in regulating proliferation by directly repressing cyclin-dependent kinase inhibitors, including the p27Kip1 promoter. Inhibits TGF-beta signaling through interaction with SMAD4 and NCOR1. Binds to chromatin DNA via its DACHbox-N domain.
• Tissue Specificity: Widely expressed. Isoform 2 is found in brain, heart, kidney, liver, leukocytes and spleen. Isoform 3 is found in liver and heart. Isoform 4 is found in spleen.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Posttranslational Modification	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Posttranslational Modification	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[12]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
leukaemia	DISS7D1V	Strong	Biomarker	[15]
Leukemia	DISNAKFL	Strong	Biomarker	[15]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[16]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[17]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Neoplasm of esophagus	DISOLKAQ	Strong	Posttranslational Modification	[5]
Neurofibromatosis type 1	DIS53JH9	Strong	Genetic Variation	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Oral cancer	DISLD42D	Strong	Posttranslational Modification	[21]
Oral cavity carcinoma	DISZXMVL	Strong	Posttranslational Modification	[21]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[22]
Postaxial polydactyly type A	DIS4IIPW	Strong	Biomarker	[23]
Prediabetes syndrome	DISH2I53	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[24]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[8]
Renal dysplasia	DIS3DFGD	Strong	Genetic Variation	[25]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[12]
Glioma	DIS5RPEH	moderate	Altered Expression	[26]
Invasive breast carcinoma	DISANYTW	moderate	Altered Expression	[27]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[28]
Lung cancer	DISCM4YA	moderate	Posttranslational Modification	[29]
Lung carcinoma	DISTR26C	moderate	Posttranslational Modification	[29]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[30]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[31]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[32]
Male breast carcinoma	DISUNQ2Q	Limited	Altered Expression	[33]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[33]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[34]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	Dachshund homolog 1 (DACH1) increases the Hypersensitivity ADR of Phenytoin.	[46]

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 Dachshund homolog 1 (DACH1).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dachshund homolog 1 (DACH1).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dachshund homolog 1 (DACH1).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Dachshund homolog 1 (DACH1).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dachshund homolog 1 (DACH1).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dachshund homolog 1 (DACH1).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Dachshund homolog 1 (DACH1).	[41]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Dachshund homolog 1 (DACH1).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dachshund homolog 1 (DACH1).	[44]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dachshund homolog 1 (DACH1).	[41]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Dachshund homolog 1 (DACH1).	[45]

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 Dachshund homolog 1 (DACH1).	[43]

References

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• [2] Dachshund Depletion Disrupts Mammary Gland Development and Diverts the Composition of the Mammary Gland Progenitor Pool.Stem Cell Reports. 2019 Jan 8;12(1):135-151. doi: 10.1016/j.stemcr.2018.11.010. Epub 2018 Dec 13.
• [3] DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth.Mol Cell Biol. 2006 Oct;26(19):7116-29. doi: 10.1128/MCB.00268-06.
• [4] A comprehensive look at transcription factor gene expression changes in colorectal adenomas.BMC Cancer. 2014 Jan 29;14:46. doi: 10.1186/1471-2407-14-46.
• [5] Silencing DACH1 promotes esophageal cancer growth by inhibiting TGF- signaling.PLoS One. 2014 Apr 17;9(4):e95509. doi: 10.1371/journal.pone.0095509. eCollection 2014.
• [6] Familial young-onset diabetes, pre-diabetes and cardiovascular disease are associated with genetic variants of DACH1 in Chinese.PLoS One. 2014 Jan 20;9(1):e84770. doi: 10.1371/journal.pone.0084770. eCollection 2014.
• [7] A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet. 2007 Aug;39(8):995-9. doi: 10.1038/ng2101. Epub 2007 Jul 15.
• [8] Identification of novel epigenetic markers for clear cell renal cell carcinoma.J Urol. 2008 Sep;180(3):1126-30. doi: 10.1016/j.juro.2008.04.137. Epub 2008 Jul 18.
• [9] MicroRNA-552 promotes tumor cell proliferation and migration by directly targeting DACH1 via the Wnt/-catenin signaling pathway in colorectal cancer.Oncol Lett. 2017 Sep;14(3):3795-3802. doi: 10.3892/ol.2017.6600. Epub 2017 Jul 18.
• [10] Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer.Epigenetics. 2013 Dec;8(12):1373-83. doi: 10.4161/epi.26781. Epub 2013 Oct 22.
• [11] DACH1 suppresses epithelial to mesenchymal transition (EMT) through Notch1 pathway and reverses progestin resistance in endometrial carcinoma.Cancer Med. 2019 Aug;8(9):4380-4388. doi: 10.1002/cam4.2317. Epub 2019 Jun 18.
• [12] Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF- signalling.J Cell Mol Med. 2014 Dec;18(12):2499-511. doi: 10.1111/jcmm.12325. Epub 2014 Jun 9.
• [13] Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples.Cancer Sci. 2008 Nov;99(11):2193-9. doi: 10.1111/j.1349-7006.2008.00935.x. Epub 2008 Jan 11.
• [14] SIX1 and DACH1 influence the proliferation and apoptosis of hepatocellular carcinoma through regulating p53.Cancer Biol Ther. 2018 May 4;19(5):381-390. doi: 10.1080/15384047.2018.1423920. Epub 2018 Feb 12.
• [15] Intraplatform reproducibility and technical precision of gene expression profiling in 4 laboratories investigating 160 leukemia samples: the DACH study.Clin Chem. 2008 Oct;54(10):1705-15. doi: 10.1373/clinchem.2008.108506. Epub 2008 Aug 21.
• [16] Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates.Cancer Med. 2019 Nov;8(15):6717-6729. doi: 10.1002/cam4.2493. Epub 2019 Sep 10.
• [17] Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.Oncogene. 2010 Jan 21;29(3):368-79. doi: 10.1038/onc.2009.360. Epub 2009 Nov 9.
• [18] Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBP and GATA-1 in myeloid leukemia with MLL-AF9.Biochem Biophys Res Commun. 2012 Sep 28;426(3):299-305. doi: 10.1016/j.bbrc.2012.08.048. Epub 2012 Aug 17.
• [19] Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network.Adv Cancer Res. 2019;141:1-42. doi: 10.1016/bs.acr.2018.12.001. Epub 2019 Jan 16.
• [20] Gut microbiota composition correlates with changes in body fat content due to weight loss.Benef Microbes. 2015;6(4):431-9. doi: 10.3920/BM2014.0104. Epub 2015 Feb 12.
• [21] The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival.Tumour Biol. 2015 Apr;36(4):2855-61. doi: 10.1007/s13277-014-2913-x. Epub 2014 Dec 7.
• [22] Inhibition of DACH1 activity by short hairpin RNA represses cell proliferation and tumor invasion in pancreatic cancer.Oncol Rep. 2016 Aug;36(2):745-54. doi: 10.3892/or.2016.4843. Epub 2016 Jun 2.
• [23] DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue.Genomics. 2001 Sep;77(1-2):18-26. doi: 10.1006/geno.2001.6618.
• [24] The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth.Cancer Res. 2009 Apr 15;69(8):3347-55. doi: 10.1158/0008-5472.CAN-08-3821. Epub 2009 Apr 7.
• [25] Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia.Nephrol Dial Transplant. 2013 Jan;28(1):227-32. doi: 10.1093/ndt/gfs539. Epub 2012 Dec 21.
• [26] MicroRNA-6807-3p promotes the tumorigenesis of glioma by targeting downstream DACH1.Brain Res. 2019 Apr 1;1708:47-57. doi: 10.1016/j.brainres.2018.12.008. Epub 2018 Dec 5.
• [27] Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide.J Biol Chem. 2016 Jun 24;291(26):13495-508. doi: 10.1074/jbc.M116.715219. Epub 2016 Apr 29.
• [28] Effect of DACH1 on proliferation and invasion of laryngeal squamous cell carcinoma.Head Face Med. 2018 Sep 27;14(1):20. doi: 10.1186/s13005-018-0177-1.
• [29] Alteration of DACH1 methylation patterns in lung cancer contributes to cell proliferation and migration.Biochem Cell Biol. 2018 Oct;96(5):602-609. doi: 10.1139/bcb-2017-0279. Epub 2018 Mar 28.
• [30] DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis.J Hematol Oncol. 2018 Apr 10;11(1):53. doi: 10.1186/s13045-018-0597-1.
• [31] Identification of candidate genes or microRNAs associated with the lymph node metastasis of SCLC.Cancer Cell Int. 2018 Oct 19;18:161. doi: 10.1186/s12935-018-0653-5. eCollection 2018.
• [32] Genome-wide association and functional follow-up reveals new loci for kidney function.PLoS Genet. 2012;8(3):e1002584. doi: 10.1371/journal.pgen.1002584. Epub 2012 Mar 29.
• [33] Dachshund 1 is Differentially Expressed Between Male and Female Breast Cancer: A Matched Case-Control Study of Clinical Characteristics and Prognosis.Clin Breast Cancer. 2018 Oct;18(5):e875-e882. doi: 10.1016/j.clbc.2018.01.011. Epub 2018 Feb 2.
• [34] MicroRNA-200c promotes tumor cell proliferation and migration by directly targeting dachshund family transcription factor 1 by the Wnt/-catenin signaling pathway in nasopharyngeal carcinoma.Anticancer Drugs. 2019 Mar;30(3):218-224. doi: 10.1097/CAD.0000000000000713.
• [35] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [36] 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.
• [37] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [38] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [39] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [40] 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.
• [41] 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.
• [42] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [43] 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.
• [44] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [45] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [46] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.