Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTARP5SQ)

• DOT Name: Homeobox protein DLX-3 (DLX3)
• Gene Name: DLX3
• Related Disease:
  Fetal growth restriction
  Hypophosphatasia
  Neoplasm
  Acute lymphocytic leukaemia
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Dentinogenesis imperfecta
  Depression
  Dermatitis
  Endometriosis
  Intellectual disability
  Leukemia
  Osteogenesis imperfecta
  Small lymphocytic lymphoma
  Tricho-dento-osseous syndrome
  Type-1/2 diabetes
  X-linked Opitz G/BBB syndrome
  Amelogenesis imperfecta
  Choriocarcinoma
  Skin cancer
  Squamous cell carcinoma
  Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism
  Cutaneous squamous cell carcinoma
  Ectodermal dysplasia
  Limb-mammary syndrome
• UniProt ID: DLX3_HUMAN
• PDB ID: 4XRS
• Pfam ID: PF12413 ; PF00046
• Sequence:
  MSGSFDRKLSSILTDISSSLSCHAGSKDSPTLPESSVTDLGYYSAPQHDYYSGQPYGQTV
  NPYTYHHQFNLNGLAGTGAYSPKSEYTYGASYRQYGAYREQPLPAQDPVSVKEEPEAEVR
  MVNGKPKKVRKPRTIYSSYQLAALQRRFQKAQYLALPERAELAAQLGLTQTQVKIWFQNR
  RSKFKKLYKNGEVPLEHSPNNSDSMACNSPPSPALWDTSSHSTPAPARSQLPPPLPYSAS
  PSYLDDPTNSWYHAQNLSGPHLQQQPPQPATLHHASPGPPPNPGAVY
• Function: Transcriptional activator. Activates transcription of GNRHR, via binding to the downstream activin regulatory element (DARE) in the gene promoter.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fetal growth restriction	DIS5WEJ5	Definitive	Altered Expression	[1]
Hypophosphatasia	DISCQ0O2	Definitive	Genetic Variation	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[4]
Dentinogenesis imperfecta	DISJLZU4	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Dermatitis	DISY5SZC	Strong	Biomarker	[7]
Endometriosis	DISX1AG8	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Leukemia	DISNAKFL	Strong	Altered Expression	[4]
Osteogenesis imperfecta	DIS7XQSD	Strong	Biomarker	[9]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[4]
Tricho-dento-osseous syndrome	DISXZOGV	Strong	Autosomal dominant	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[5]
X-linked Opitz G/BBB syndrome	DISQ14EC	Strong	Biomarker	[11]
Amelogenesis imperfecta	DISGYR9E	moderate	Genetic Variation	[12]
Choriocarcinoma	DISDBVNL	moderate	Biomarker	[13]
Skin cancer	DISTM18U	moderate	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[15]
Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism	DISIKTCU	Supportive	Autosomal dominant	[10]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[16]
Ectodermal dysplasia	DISLRS4M	Limited	Genetic Variation	[17]
Limb-mammary syndrome	DIS7H4FP	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Homeobox protein DLX-3 (DLX3).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein DLX-3 (DLX3).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein DLX-3 (DLX3).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Homeobox protein DLX-3 (DLX3).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein DLX-3 (DLX3).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Homeobox protein DLX-3 (DLX3).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Homeobox protein DLX-3 (DLX3).	[27]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Homeobox protein DLX-3 (DLX3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein DLX-3 (DLX3).	[24]

References

• [1] Altered placental tryptophan metabolic pathway in human fetal growth restriction.Placenta. 2017 Apr;52:62-70. doi: 10.1016/j.placenta.2017.02.013. Epub 2017 Feb 16.
• [2] Developmental biology and genetics of dental malformations.Orthod Craniofac Res. 2007 May;10(2):45-52. doi: 10.1111/j.1601-6343.2007.00384.x.
• [3] Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review.Mol Imaging Biol. 2020 Aug;22(4):805-819. doi: 10.1007/s11307-019-01430-6.
• [4] Down-regulation of DLX3 expression in MLL-AF4 childhood lymphoblastic leukemias is mediated by promoter region hypermethylation.Oncol Rep. 2007 Aug;18(2):417-23.
• [5] IDO and TDO as a potential therapeutic target in different types of depression.Metab Brain Dis. 2018 Dec;33(6):1787-1800. doi: 10.1007/s11011-018-0290-7. Epub 2018 Jul 16.
• [6] Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta.Arch Oral Biol. 2001 May;46(5):459-70. doi: 10.1016/s0003-9969(00)00130-8.
• [7] Epidermal ablation of Dlx3 is linked to IL-17-associated skin inflammation.Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11566-71. doi: 10.1073/pnas.1019658108. Epub 2011 Jun 27.
• [8] lncRNA/mRNA profiling of endometriosis rat uterine tissues during the implantation window.Int J Mol Med. 2019 Dec;44(6):2145-2160. doi: 10.3892/ijmm.2019.4370. Epub 2019 Oct 14.
• [9] Osteogenesis imperfecta, tricho-dento-osseous syndrome and intellectual disability: a familial case with 17q21.33-q22 (COL1A1 and DLX3) deletion and 7q32.3-q33 duplication resulting from a reciprocal interchromosomal insertion.Am J Med Genet A. 2013 Oct;161A(10):2504-11. doi: 10.1002/ajmg.a.36122. Epub 2013 Aug 15.
• [10] DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism. Am J Med Genet A. 2005 Mar 1;133A(2):138-41. doi: 10.1002/ajmg.a.30521.
• [11] BMP-2 induced Dspp transcription is mediated by Dlx3/Osx signaling pathway in odontoblasts.Sci Rep. 2017 Sep 7;7(1):10775. doi: 10.1038/s41598-017-10908-8.
• [12] Novel DLX3 variants in amelogenesis imperfecta with attenuated tricho-dento-osseous syndrome.Oral Dis. 2019 Jan;25(1):182-191. doi: 10.1111/odi.12955. Epub 2018 Sep 9.
• [13] A role for CCAAT/enhancer-binding protein beta in the basal regulation of the distal-less 3 gene promoter in placental cells.Endocrinology. 2004 Mar;145(3):1096-105. doi: 10.1210/en.2003-0777. Epub 2003 Dec 11.
• [14] Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?.Int J Mol Sci. 2019 Jul 19;20(14):3541. doi: 10.3390/ijms20143541.
• [15] The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth.Oncogene. 2016 Jun 16;35(24):3114-24. doi: 10.1038/onc.2015.380. Epub 2015 Nov 2.
• [16] A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation.Cell Death Differ. 2017 Apr;24(4):717-730. doi: 10.1038/cdd.2017.5. Epub 2017 Feb 10.
• [17] A dominant mutation etiologic for human tricho-dento-osseous syndrome impairs the ability of DLX3 to downregulate Np63.J Cell Physiol. 2011 Aug;226(8):2189-97. doi: 10.1002/jcp.22553.
• [18] Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias.Development. 2007 Jan;134(1):13-8. doi: 10.1242/dev.02703.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.