Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT33KEUZ)

• DOT Name: Dachshund homolog 2 (DACH2)
• Synonyms: Dach2
• Gene Name: DACH2
• Related Disease:
  Neoplasm
  Transitional cell carcinoma
  Urothelial carcinoma
• UniProt ID: DACH2_HUMAN
• Pfam ID: PF02437
• Sequence:
  MAVSASPVISATSSGAGVPGGLFRAEPLYSTPREPPRLTPNMINSFVVNNHSNSAGGGGR
  GNTNTNECRMVDMHGMKVASFLMDGQELICLPQVFDLFLKHLVGGLHTVYTKLKRLDISP
  VVCTVEQVRILRGLGAIQPGVNRCKLITRKDFETLFTDCTNARRKRQMTRKQAVNSSRPG
  RPPKRSLGVLQENARLLTHAVPGLLSPGLITPTGITAAAMAEAMKLQKMKLMAMNTLQGN
  GSQNGTESEPDDLNSNTGGSESSWDKDKMQSPFAAPGPQHGIAHAALAGQPGIGGAPTLN
  PLQQNHLLTNRLDLPFMMMPHPLLPVSLPPASVAMAMNQMNHLNTIANMAAAAQIHSPLS
  RAGTSVIKERIPESPSPAPSLEENHRPGSQTSSHTSSSVSSSPSQMDHHLERMEEVPVQI
  PIMKSPLDKIQLTPGQALPAGFPGPFIFADSLSSVETLLTNIQGLLKVALDNARIQEKQI
  QQEKKELRLELYREREIRENLERQLAVELQSRTTMQKRLKKEKKTKRKLQEALEFESKRR
  EQVEQALKQATTSDSGLRMLKDTGIPDIEIENNGTPHDSAAMQGGNYYCLEMAQQLYSA
• Function: Transcription factor that is involved in regulation of organogenesis. Seems to be a regulator for SIX1 and SIX6. Seems to act as a corepressor of SIX6 in regulating proliferation by directly repressing cyclin-dependent kinase inhibitors, including the p27Kip1 promoter. Is recruited with SIX6 to the p27Kip1 promoter in embryonal retina. SIX6 corepression seems also to involve NCOR1, TBL1, HDAC1 and HDAC3. May be involved together with PAX3, SIX1, and EYA2 in regulation of myogenesis. In the developing somite, expression of DACH2 and PAX3 is regulated by the overlying ectoderm, and DACH2 and PAX3 positively regulate each other's expression. Probably binds to DNA via its DACHbox-N domain.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[1]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[1]

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 Dachshund homolog 2 (DACH2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dachshund homolog 2 (DACH2).	[7]

6 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 Dachshund homolog 2 (DACH2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dachshund homolog 2 (DACH2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dachshund homolog 2 (DACH2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Dachshund homolog 2 (DACH2).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dachshund homolog 2 (DACH2).	[8]
Manganese	DMKT129	Investigative	Manganese increases the expression of Dachshund homolog 2 (DACH2).	[9]

References

• [1] Prospective validation of DACH2 as a novel biomarker for prediction of metastasis and prognosis in muscle-invasive urothelial carcinoma of the bladder.Biochem Biophys Res Commun. 2015 Apr 10;459(3):416-23. doi: 10.1016/j.bbrc.2015.02.119. Epub 2015 Mar 2.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.