Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7BH057)

• DOT Name: Homeobox protein DLX-1 (DLX1)
• Gene Name: DLX1
• Related Disease:
  Advanced cancer
  Autism
  Autism spectrum disorder
  Bipolar disorder
  Brain disease
  Cervical cancer
  Cervical carcinoma
  Cleft lip/palate
  Epilepsy
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Progressive supranuclear palsy
  Prostate neoplasm
  Schizophrenia
  Prostate cancer
  Prostate carcinoma
  Intellectual disability
  Squamous cell carcinoma
• UniProt ID: DLX1_HUMAN
• Pfam ID: PF00046
• Sequence:
  MTMTTMPESLNSPVSGKAVFMEFGPPNQQMSPSPMSHGHYSMHCLHSAGHSQPDGAYSSA
  SSFSRPLGYPYVNSVSSHASSPYISSVQSYPGSASLAQSRLEDPGADSEKSTVVEGGEVR
  FNGKGKKIRKPRTIYSSLQLQALNRRFQQTQYLALPERAELAASLGLTQTQVKIWFQNKR
  SKFKKLMKQGGAALEGSALANGRALSAGSPPVPPGWNPNSSSGKGSGGNAGSYIPSYTSW
  YPSAHQEAMQQPQLM
• Function: Plays a role as a transcriptional activator or repressor. Inhibits several cytokine signaling pathways, such as TGFB1, activin-A/INHBA and BMP4 by interfering with the transcriptional stimulatory activity of transcription factors, such as MSX2, FAST2, SMAD2 and SMAD3 during hematopoietic cell differentiation. 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 and may be involved in the early development of diencephalic subdivisions.
• Tissue Specificity: Expressed in hematopoietic cell lines.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[4]
Brain disease	DIS6ZC3X	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Biomarker	[6]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[7]
Epilepsy	DISBB28L	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Progressive supranuclear palsy	DISO5KRQ	Strong	Altered Expression	[10]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	moderate	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[12]
Intellectual disability	DISMBNXP	Limited	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[14]

12 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-1 (DLX1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein DLX-1 (DLX1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein DLX-1 (DLX1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein DLX-1 (DLX1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein DLX-1 (DLX1).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Homeobox protein DLX-1 (DLX1).	[17]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Homeobox protein DLX-1 (DLX1).	[17]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Homeobox protein DLX-1 (DLX1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeobox protein DLX-1 (DLX1).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homeobox protein DLX-1 (DLX1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein DLX-1 (DLX1).	[23]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Homeobox protein DLX-1 (DLX1).	[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 decreases the methylation of Homeobox protein DLX-1 (DLX1).	[22]

References

• [1] DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-/SMAD4 signaling.Oncogene. 2017 Mar;36(10):1404-1416. doi: 10.1038/onc.2016.307. Epub 2016 Sep 5.
• [2] 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.
• [3] Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders.Am J Med Genet B Neuropsychiatr Genet. 2011 Mar;156(2):233-9. doi: 10.1002/ajmg.b.31148. Epub 2010 Dec 16.
• [4] Decreased thalamic expression of the homeobox gene DLX1 in psychosis.Arch Gen Psychiatry. 2003 Sep;60(9):869-74. doi: 10.1001/archpsyc.60.9.869.
• [5] 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.
• [6] Performance of a DNA methylation marker panel using liquid-based cervical scrapes to detect cervical cancer and its precancerous stages.BMC Cancer. 2018 Dec 3;18(1):1197. doi: 10.1186/s12885-018-5125-8.
• [7] DLX1 and MMP3 contribute to oral clefts with and without positive family history of cancer.Arch Oral Biol. 2015 Feb;60(2):223-8. doi: 10.1016/j.archoralbio.2014.10.002. Epub 2014 Oct 22.
• [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] MicroRNA-539 functions as a tumour suppressor in prostate cancer via the TGF-/Smad4 signalling pathway by down-regulating DLX1.J Cell Mol Med. 2019 Sep;23(9):5934-5948. doi: 10.1111/jcmm.14402. Epub 2019 Jul 12.
• [10] Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1.Nat Commun. 2018 Jul 26;9(1):2929. doi: 10.1038/s41467-018-05325-y.
• [11] Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits.Epigenetics Chromatin. 2016 Nov 9;9:50. doi: 10.1186/s13072-016-0102-4. eCollection 2016.
• [12] Multicenter Optimization and Validation of a 2-Gene mRNA Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy.J Urol. 2019 Aug;202(2):256-263. doi: 10.1097/JU.0000000000000293. Epub 2019 Jul 8.
• [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] Long noncoding RNA TUG1 regulates the development of oral squamous cell carcinoma through sponging miR-524-5p to mediate DLX1 expression as a competitive endogenous RNA.J Cell Physiol. 2019 Nov;234(11):20206-20216. doi: 10.1002/jcp.28620. Epub 2019 Apr 13.
• [15] 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.
• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [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] 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.
• [24] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.