Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKC2DQ0)

• DOT Name: Homeobox protein DLX-2 (DLX2)
• Gene Name: DLX2
• Related Disease:
  Axenfeld-Rieger syndrome
  Rieger anomaly
  Adult glioblastoma
  Advanced cancer
  Al-Raqad syndrome
  Autism spectrum disorder
  Brain disease
  Breast cancer
  Breast carcinoma
  Epilepsy
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Lymphoproliferative syndrome
  Neoplasm
  Autism
  Metastatic malignant neoplasm
  Intellectual disability
• UniProt ID: DLX2_HUMAN
• Pfam ID: PF12413 ; PF00046
• Sequence:
  MTGVFDSLVADMHSTQIAASSTYHQHQQPPSGGGAGPGGNSSSSSSLHKPQESPTLPVST
  ATDSSYYTNQQHPAGGGGGGGSPYAHMGSYQYQASGLNNVPYSAKSSYDLGYTAAYTSYA
  PYGTSSSPANNEPEKEDLEPEIRIVNGKPKKVRKPRTIYSSFQLAALQRRFQKTQYLALP
  ERAELAASLGLTQTQVKIWFQNRRSKFKKMWKSGEIPSEQHPGASASPPCASPPVSAPAS
  WDFGVPQRMAGGGGPGSGGSGAGSSGSSPSSAASAFLGNYPWYHQTSGSASHLQATAPLL
  HPTQTPQPHHHHHHHGGGGAPVSAGTIF
• Function: Acts as a transcriptional activator. Activates transcription of CGA/alpha-GSU, via binding to the downstream activin regulatory element (DARE) in the gene promoter. Plays a role in terminal differentiation of interneurons, such as amacrine and bipolar cells in the developing retina. Likely to play a regulatory role in the development of the ventral forebrain. May play a role in craniofacial patterning and morphogenesis.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Axenfeld-Rieger syndrome	DIS6XY4L	Definitive	Genetic Variation	[1]
Rieger anomaly	DISNBLZ5	Definitive	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Al-Raqad syndrome	DISR2J8Q	Strong	Altered Expression	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Brain disease	DIS6ZC3X	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Epilepsy	DISBB28L	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
Lymphoproliferative syndrome	DISMVL8O	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Autism	DISV4V1Z	moderate	Genetic Variation	[5]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[12]
Intellectual disability	DISMBNXP	Limited	Biomarker	[13]

17 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-2 (DLX2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Homeobox protein DLX-2 (DLX2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein DLX-2 (DLX2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homeobox protein DLX-2 (DLX2).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Homeobox protein DLX-2 (DLX2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeobox protein DLX-2 (DLX2).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein DLX-2 (DLX2).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Homeobox protein DLX-2 (DLX2).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein DLX-2 (DLX2).	[22]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Homeobox protein DLX-2 (DLX2).	[23]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Homeobox protein DLX-2 (DLX2).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeobox protein DLX-2 (DLX2).	[25]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homeobox protein DLX-2 (DLX2).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Homeobox protein DLX-2 (DLX2).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Homeobox protein DLX-2 (DLX2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein DLX-2 (DLX2).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Homeobox protein DLX-2 (DLX2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Homeobox protein DLX-2 (DLX2).	[29]

References

• [1] A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome. Hum Mol Genet. 2002 Apr 1;11(7):743-53. doi: 10.1093/hmg/11.7.743.
• [2] Upregulation of DLX2 confers a poor prognosis in glioblastoma patients by inducing a proliferative phenotype.Curr Mol Med. 2013 Mar;13(3):438-45.
• [3] Smad2/3-Regulated Expression of DLX2 Is Associated with Radiation-Induced Epithelial-Mesenchymal Transition and Radioresistance of A549 and MDA-MB-231 Human Cancer Cell Lines.PLoS One. 2016 Jan 22;11(1):e0147343. doi: 10.1371/journal.pone.0147343. eCollection 2016.
• [4] Protein kinase C phosphorylation modulates N- and C-terminal regulatory activities of the PITX2 homeodomain protein.Biochemistry. 2005 Mar 15;44(10):3942-54. doi: 10.1021/bi048362x.
• [5] The DLX1and DLX2 genes and susceptibility to autism spectrum disorders.Eur J Hum Genet. 2009 Feb;17(2):228-35. doi: 10.1038/ejhg.2008.148. Epub 2008 Aug 27.
• [6] GABAergic Interneuron Differentiation in the Basal Forebrain Is Mediated through Direct Regulation of Glutamic Acid Decarboxylase Isoforms by Dlx Homeobox Transcription Factors.J Neurosci. 2017 Sep 6;37(36):8816-8829. doi: 10.1523/JNEUROSCI.2125-16.2017. Epub 2017 Aug 8.
• [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] Developmental lineage of cell types in cortical dysplasia with balloon cells.Brain. 2007 Sep;130(Pt 9):2267-76. doi: 10.1093/brain/awm175.
• [9] Actinidia chinensis Planch root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting epithelial-mesenchymal transition.J Ethnopharmacol. 2019 Mar 1;231:474-485. doi: 10.1016/j.jep.2018.11.014. Epub 2018 Nov 8.
• [10] TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation.PLoS Pathog. 2015 May 21;11(5):e1004890. doi: 10.1371/journal.ppat.1004890. eCollection 2015 May.
• [11] Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch.Oncotarget. 2016 Feb 16;7(7):7925-39. doi: 10.18632/oncotarget.6879.
• [12] p53-R273H upregulates neuropilin-2 to promote cell mobility and tumor metastasis.Cell Death Dis. 2017 Aug 10;8(8):e2995. doi: 10.1038/cddis.2017.376.
• [13] A patient with five chromosomal rearrangements and a 2q31.1 microdeletion.Clin Chim Acta. 2014 Mar 20;430:129-33. doi: 10.1016/j.cca.2014.01.002. Epub 2014 Jan 9.
• [14] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [20] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [21] 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.
• [22] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [23] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [24] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [27] 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.
• [28] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] 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.
• [31] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.