Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLWVCN4)

• DOT Name: Homeobox protein DLX-4 (DLX4)
• Synonyms: Beta protein 1; Homeobox protein DLX-7; Homeobox protein DLX-8
• Gene Name: DLX4
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Advanced cancer
  Anxiety
  Anxiety disorder
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Bipolar I disorder
  Breast cancer
  Breast carcinoma
  Childhood myelodysplastic syndrome
  Choriocarcinoma
  Cleft lip/palate
  Colon cancer
  Colon carcinoma
  Depression
  Eating disorder
  Estrogen-receptor positive breast cancer
  Exanthem
  Familial Alzheimer disease
  Hepatocellular carcinoma
  Hypercholesterolemia, autosomal dominant, type B
  Hyperlipidemia, familial combined, LPL related
  Inflammatory breast cancer
  Leukemia
  Lung neoplasm
  Major depressive disorder
  Mood disorder
  Myelodysplastic syndrome
  Neoplasm
  Prostate neoplasm
  Tricho-dento-osseous syndrome
  Fetal growth restriction
  Squamous cell carcinoma
  Acute myelogenous leukaemia
  Breast neoplasm
  Schizoaffective disorder
  Amyloidosis
  Orofacial cleft 15
  Thalassemia
• UniProt ID: DLX4_HUMAN
• Pfam ID: PF00046
• Sequence:
  MTSLPCPLPGRDASKAVFPDLAPVPSVAAAYPLGLSPTTAASPNLSYSRPYGHLLSYPYT
  EPANPGDSYLSCQQPAALSQPLCGPAEHPQELEADSEKPRLSPEPSERRPQAPAKKLRKP
  RTIYSSLQLQHLNQRFQHTQYLALPERAQLAAQLGLTQTQVKIWFQNKRSKYKKLLKQNS
  GGQEGDFPGRTFSVSPCSPPLPSLWDLPKAGTLPTSGYGNSFGAWYQHHSSDVLASPQMM
• Function: May play a role in determining the production of hemoglobin S. May act as a repressor. During embryonic development, plays a role in palatogenesis.
• Tissue Specificity: Expressed in leukemia cells and placenta. Also expressed in kidney and fetal liver.

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Altered Expression	[1]
Ovarian cancer	DISZJHAP	Definitive	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Bipolar I disorder	DISD09EH	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Posttranslational Modification	[8]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[9]
Cleft lip/palate	DIS14IG3	Strong	GermlineCausalMutation	[10]
Colon cancer	DISVC52G	Strong	Altered Expression	[11]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Eating disorder	DISVGXN0	Strong	Biomarker	[13]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[14]
Exanthem	DISAFOQN	Strong	Biomarker	[5]
Familial Alzheimer disease	DISE75U4	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Hypercholesterolemia, autosomal dominant, type B	DISNFXJZ	Strong	Biomarker	[16]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Biomarker	[16]
Inflammatory breast cancer	DIS3QRWA	Strong	Altered Expression	[17]
Leukemia	DISNAKFL	Strong	Biomarker	[18]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[19]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[13]
Mood disorder	DISLVMWO	Strong	Biomarker	[20]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[21]
Tricho-dento-osseous syndrome	DISXZOGV	Strong	Genetic Variation	[22]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[23]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[24]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Altered Expression	[25]
Breast neoplasm	DISNGJLM	Disputed	Biomarker	[14]
Schizoaffective disorder	DISLBW6B	Disputed	Biomarker	[26]
Amyloidosis	DISHTAI2	Limited	Altered Expression	[27]
Orofacial cleft 15	DISRXKC7	Limited	Autosomal dominant	[10]
Thalassemia	DIS76XZB	Limited	Biomarker	[27]

18 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-4 (DLX4).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein DLX-4 (DLX4).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein DLX-4 (DLX4).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein DLX-4 (DLX4).	[31]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeobox protein DLX-4 (DLX4).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein DLX-4 (DLX4).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein DLX-4 (DLX4).	[34]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein DLX-4 (DLX4).	[35]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Homeobox protein DLX-4 (DLX4).	[36]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Homeobox protein DLX-4 (DLX4).	[37]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Homeobox protein DLX-4 (DLX4).	[38]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Homeobox protein DLX-4 (DLX4).	[39]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Homeobox protein DLX-4 (DLX4).	[40]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Homeobox protein DLX-4 (DLX4).	[41]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Homeobox protein DLX-4 (DLX4).	[42]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Homeobox protein DLX-4 (DLX4).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein DLX-4 (DLX4).	[45]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Homeobox protein DLX-4 (DLX4).	[46]

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-4 (DLX4).	[44]

References

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• [2] Overexpression of BP1, an isoform of Homeobox Gene DLX4, promotes cell proliferation, migration and predicts poor prognosis in endometrial cancer.Gene. 2019 Jul 30;707:216-223. doi: 10.1016/j.gene.2019.05.028. Epub 2019 May 15.
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• [8] Hypermethylation of DLX4 predicts poor clinical outcome in patients with myelodysplastic syndrome.Clin Chem Lab Med. 2016 May;54(5):865-71. doi: 10.1515/cclm-2015-0536.
• [9] A distal-less class homeobox gene, DLX4, is a candidate for regulating epithelial-mesenchymal cell interactions in the human placenta.Placenta. 1998 Jan;19(1):87-93. doi: 10.1016/s0143-4004(98)90103-5.
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• [11] Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma.Mol Med Rep. 2015 Jul;12(1):1375-80. doi: 10.3892/mmr.2015.3554. Epub 2015 Mar 27.
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• [17] Homeoprotein DLX4 expression is increased in inflammatory breast cancer cases from an urban African-American population.Oncotarget. 2018 Jul 27;9(58):31253-31263. doi: 10.18632/oncotarget.25790. eCollection 2018 Jul 27.
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• [22] Tricho-dento-osseous syndrome and amelogenesis imperfecta with taurodontism are genetically distinct conditions.Clin Genet. 1999 Jul;56(1):35-40. doi: 10.1034/j.1399-0004.1999.550105.x.
• [23] Homeobox gene DLX4 expression is increased in idiopathic human fetal growth restriction.Mol Hum Reprod. 2006 Dec;12(12):763-9. doi: 10.1093/molehr/gal087. Epub 2006 Oct 24.
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• [32] 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.
• [33] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [34] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
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• [37] Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells. J Cell Biochem. 2003 Jul 1;89(4):755-70.
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• [39] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [40] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [41] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [42] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [43] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
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• [45] 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.
• [46] 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.