Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0FIJHY)

• DOT Name: Homeobox protein DLX-6 (DLX6)
• Gene Name: DLX6
• Related Disease:
  Nervous system disease
  Cleft palate
  Congenital deformities of limbs
  Esophageal squamous cell carcinoma
  Isolated cleft palate
  Isolated Pierre-Robin syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Rapp-Hodgkin syndrome
  T-cell lymphoma
  Trichohepatoenteric syndrome
  Female hypogonadism
  Split hand-foot malformation
  Autism spectrum disorder
  Rett syndrome
  Split hand-foot malformation 1 with sensorineural hearing loss
• UniProt ID: DLX6_HUMAN
• Pfam ID: PF00046
• Sequence:
  MSHSQHSPYLQSYHNSSAAAQTRGDDTDQQKTTVIENGEIRFNGKGKKIRKPRTIYSSLQ
  LQALNHRFQQTQYLALPERAELAASLGLTQTQVKIWFQNKRSKFKKLLKQGSNPHESDPL
  QGSAALSPRSPALPPVWDVSASAKGVSMPPNSYMPGYSHWYSSPHQDTMQRPQMM
• Reactome Pathway: Regulation of RUNX2 expression and activity (R-HSA-8939902)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Altered Expression	[1]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[2]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[2]
Isolated Pierre-Robin syndrome	DISVEHG7	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Rapp-Hodgkin syndrome	DISCNGW9	Strong	Genetic Variation	[7]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[8]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[9]
Female hypogonadism	DISWASB4	moderate	Biomarker	[10]
Split hand-foot malformation	DIS8PKGD	Supportive	Autosomal dominant	[11]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[12]
Rett syndrome	DISGG5UV	Limited	Altered Expression	[13]
Split hand-foot malformation 1 with sensorineural hearing loss	DISEHK38	Limited	Biomarker	[11]

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 Homeobox protein DLX-6 (DLX6).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein DLX-6 (DLX6).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homeobox protein DLX-6 (DLX6).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein DLX-6 (DLX6).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein DLX-6 (DLX6).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein DLX-6 (DLX6).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Homeobox protein DLX-6 (DLX6).	[20]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Homeobox protein DLX-6 (DLX6).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein DLX-6 (DLX6).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Homeobox protein DLX-6 (DLX6).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein DLX-6 (DLX6).	[24]

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-6 (DLX6).	[22]

References

• [1] Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders.Front Neurosci. 2018 Mar 21;12:150. doi: 10.3389/fnins.2018.00150. eCollection 2018.
• [2] 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.
• [3] Are there CAG repeat expansion-related disorders outside the central nervous system?.Brain Res Bull. 2001 Oct-Nov 1;56(3-4):259-64. doi: 10.1016/s0361-9230(01)00663-3.
• [4] Long noncoding RNA DLX6AS1 is associated with malignant progression and promotes proliferation and invasion in esophageal squamous cell carcinoma.Mol Med Rep. 2019 Mar;19(3):1942-1950. doi: 10.3892/mmr.2018.9786. Epub 2018 Dec 21.
• [5] 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.
• [6] LncRNA DLX6-AS1 promotes the proliferation, invasion, and migration of non-small cell lung cancer cells by targeting the miR-27b-3p/GSPT1 axis.Onco Targets Ther. 2019 May 22;12:3945-3954. doi: 10.2147/OTT.S196865. eCollection 2019.
• [7] 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.
• [8] A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice.Cancer Res. 2008 Mar 1;68(5):1296-302. doi: 10.1158/0008-5472.CAN-07-3218.
• [9] 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.
• [10] 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.
• [11] A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1. Mol Syndromol. 2017 Mar;8(2):79-84. doi: 10.1159/000453350. Epub 2016 Dec 20.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency.Am J Hum Genet. 2007 Sep;81(3):492-506. doi: 10.1086/520063. Epub 2007 Aug 2.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] 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.
• [20] 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.
• [21] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.