Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein DLX-5 (DLX5)
• Gene Name: DLX5
• Related Disease:
  Neural tube defect
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Autism
  Autism spectrum disorder
  Bone development disease
  Breast cancer
  Breast carcinoma
  Craniosynostosis
  Endometriosis
  Glomerulosclerosis
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Neuralgia
  Osteoarthritis
  Osteoporosis
  Pediatric lymphoma
  Rapp-Hodgkin syndrome
  Renal fibrosis
  Rett syndrome
  Sensorineural hearing loss disorder
  Split hand-foot malformation 1 with sensorineural hearing loss
  T-cell lymphoma
  Tooth agenesis
  Trichohepatoenteric syndrome
  West syndrome
  Female hypogonadism
  Lymphoma
  Split hand-foot malformation
  Chromosomal disorder
  Cleft palate
  Epithelial ovarian cancer
  Fetal growth restriction
  Isolated cleft palate
  Lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Periodontitis
• UniProt ID: DLX5_HUMAN
• PDB ID: 2DJN; 4RDU
• Pfam ID: PF12413 ; PF00046
• Sequence:
  MTGVFDRRVPSIRSGDFQAPFQTSAAMHHPSQESPTLPESSATDSDYYSPTGGAPHGYCS
  PTSASYGKALNPYQYQYHGVNGSAGSYPAKAYADYSYASSYHQYGGAYNRVPSATNQPEK
  EVTEPEVRMVNGKPKKVRKPRTIYSSFQLAALQRRFQKTQYLALPERAELAASLGLTQTQ
  VKIWFQNKRSKIKKIMKNGEMPPEHSPSSSDPMACNSPQSPAVWEPQGSSRSLSHHPHAH
  PPTSNQSPASSYLENSASWYTSAASSINSHLPPPGSLQHPLALASGTLY
• Function: Transcriptional factor involved in bone development. Acts as an immediate early BMP-responsive transcriptional activator essential for osteoblast differentiation. Stimulates ALPL promoter activity in a RUNX2-independent manner during osteoblast differentiation. Stimulates SP7 promoter activity during osteoblast differentiation. Promotes cell proliferation by up-regulating MYC promoter activity. Involved as a positive regulator of both chondrogenesis and chondrocyte hypertrophy in the endochondral skeleton. Binds to the homeodomain-response element of the ALPL and SP7 promoter. Binds to the MYC promoter. Requires the 5'-TAATTA-3' consensus sequence for DNA-binding.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: Regulation of RUNX2 expression and activity (R-HSA-8939902)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neural tube defect	DIS5J95E	Definitive	Altered Expression	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Bone development disease	DISVKAZS	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Craniosynostosis	DIS6J405	Strong	Biomarker	[8]
Endometriosis	DISX1AG8	Strong	Biomarker	[9]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[11]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neuralgia	DISWO58J	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Osteoporosis	DISF2JE0	Strong	Biomarker	[2]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Rapp-Hodgkin syndrome	DISCNGW9	Strong	Genetic Variation	[16]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[10]
Rett syndrome	DISGG5UV	Strong	Biomarker	[2]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[17]
Split hand-foot malformation 1 with sensorineural hearing loss	DISEHK38	Strong	Autosomal dominant	[18]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[13]
Tooth agenesis	DIS1PWC7	Strong	Biomarker	[19]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[20]
West syndrome	DISLIAU9	Strong	Genetic Variation	[21]
Female hypogonadism	DISWASB4	moderate	Biomarker	[22]
Lymphoma	DISN6V4S	moderate	Biomarker	[2]
Split hand-foot malformation	DIS8PKGD	Supportive	Autosomal dominant	[23]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[24]
Cleft palate	DIS6G5TF	Limited	Genetic Variation	[25]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[3]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[26]
Isolated cleft palate	DISV80CD	Limited	Genetic Variation	[25]
Lung cancer	DISCM4YA	Limited	Altered Expression	[11]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[3]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[27]

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-5 (DLX5).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein DLX-5 (DLX5).	[29]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein DLX-5 (DLX5).	[30]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Homeobox protein DLX-5 (DLX5).	[31]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Homeobox protein DLX-5 (DLX5).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Homeobox protein DLX-5 (DLX5).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein DLX-5 (DLX5).	[35]

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 Homeobox protein DLX-5 (DLX5).	[33]

References

• [1] Posterior axis formation requires Dlx5/Dlx6 expression at the neural plate border.PLoS One. 2019 Mar 19;14(3):e0214063. doi: 10.1371/journal.pone.0214063. eCollection 2019.
• [2] Dlx5 Homeodomain:DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome.J Mol Biol. 2016 Mar 27;428(6):1130-1141. doi: 10.1016/j.jmb.2016.01.023. Epub 2016 Jan 29.
• [3] Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling.Cancer Res. 2010 Nov 15;70(22):9197-206. doi: 10.1158/0008-5472.CAN-10-1568. Epub 2010 Nov 2.
• [4] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [5] Expression analysis and mutation detection of DLX5 and DLX6 in autism.Brain Dev. 2010 Feb;32(2):98-104. doi: 10.1016/j.braindev.2008.12.021. Epub 2009 Feb 4.
• [6] Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5.Development. 1999 Sep;126(17):3795-809. doi: 10.1242/dev.126.17.3795.
• [7] Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231.BMC Cancer. 2010 Nov 25;10:649. doi: 10.1186/1471-2407-10-649.
• [8] Prevention of premature fusion of calvarial suture in GLI-Kruppel family member 3 (Gli3)-deficient mice by removing one allele of Runt-related transcription factor 2 (Runx2).J Biol Chem. 2012 Jun 15;287(25):21429-38. doi: 10.1074/jbc.M112.362145. Epub 2012 Apr 30.
• [9] Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain.J Pain Res. 2018 Apr 10;11:715-725. doi: 10.2147/JPR.S163611. eCollection 2018.
• [10] DLX5 gene regulates the Notch signaling pathway to promote glomerulosclerosis and interstitial fibrosis in uremic rats.J Cell Physiol. 2019 Dec;234(12):21825-21837. doi: 10.1002/jcp.28032. Epub 2019 Jul 11.
• [11] Gprc5a depletion enhances the risk of smoking-induced lung tumorigenesis and mortality.Biomed Pharmacother. 2019 Jun;114:108791. doi: 10.1016/j.biopha.2019.108791. Epub 2019 Mar 19.
• [12] Activation of placenta-specific transcription factor distal-less homeobox 5 predicts clinical outcome in primary lung cancer patients.Clin Cancer Res. 2008 Apr 15;14(8):2363-70. doi: 10.1158/1078-0432.CCR-07-1523.
• [13] The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling.Oncotarget. 2017 Feb 28;8(9):14941-14956. doi: 10.18632/oncotarget.14784.
• [14] Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve-injured mice.Br J Pharmacol. 2020 Mar;177(5):1187-1205. doi: 10.1111/bph.14911. Epub 2020 Feb 10.
• [15] Suitability of porcine chondrocyte micromass culture to model osteoarthritis in vitro.Mol Pharm. 2014 Jul 7;11(7):2092-105. doi: 10.1021/mp5000554. Epub 2014 Mar 27.
• [16] Rapp-Hodgkin syndrome and SHFM1 patients: delineating the p63-Dlx5/Dlx6 pathway.Gene. 2012 Apr 15;497(2):292-7. doi: 10.1016/j.gene.2012.01.088. Epub 2012 Feb 9.
• [17] Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype.Brain. 2007 Oct;130(Pt 10):2736-45. doi: 10.1093/brain/awm209.
• [18] Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J Med Genet. 2012 Jan;49(1):16-20. doi: 10.1136/jmedgenet-2011-100556. Epub 2011 Nov 25.
• [19] A novel mutation (c.1010G>T; p.R337L) in TP63 as a cause of split-hand/foot malformation with hypodontia.J Gene Med. 2019 Oct;21(10):e3122. doi: 10.1002/jgm.3122. Epub 2019 Aug 30.
• [20] Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35).Hum Genet. 2010 Jan;127(1):19-31. doi: 10.1007/s00439-009-0736-4.
• [21] Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females.Brain. 2009 Jun;132(Pt 6):1563-76. doi: 10.1093/brain/awp107. Epub 2009 May 12.
• [22] Allelic reduction of Dlx5 and Dlx6 results in early follicular depletion: a new mouse model of primary ovarian insufficiency.Hum Mol Genet. 2011 Jul 1;20(13):2642-50. doi: 10.1093/hmg/ddr166. Epub 2011 Apr 19.
• [23] Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. Eur J Hum Genet. 2014 Sep;22(9):1105-10. doi: 10.1038/ejhg.2014.7. Epub 2014 Feb 5.
• [24] Phenotypic subregions within the split-hand/foot malformation 1 locus.Hum Genet. 2016 Mar;135(3):345-57. doi: 10.1007/s00439-016-1635-0. Epub 2016 Feb 2.
• [25] A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence.PLoS Genet. 2014 Apr 3;10(4):e1004257. doi: 10.1371/journal.pgen.1004257. eCollection 2014 Apr.
• [26] The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction.Mol Hum Reprod. 2019 Sep 1;25(9):572-585. doi: 10.1093/molehr/gaz047.
• [27] Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis.Sci Rep. 2016 Sep 20;6:33666. doi: 10.1038/srep33666.
• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells. Environ Health Perspect. 2015 Jan;123(1):42-8.
• [30] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [31] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [32] Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK. Environ Toxicol. 2020 Dec;35(12):1318-1325. doi: 10.1002/tox.22996. Epub 2020 Jul 13.
• [33] 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.
• [34] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [35] 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.