Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQR4WCG)

• DOT Name: Homeobox protein Hox-D4 (HOXD4)
• Synonyms: Homeobox protein HHO.C13; Homeobox protein Hox-4B; Homeobox protein Hox-5.1
• Gene Name: HOXD4
• Related Disease:
  Acute lymphocytic leukaemia
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Glioma
  Neoplasm
  Rheumatoid arthritis
• UniProt ID: HXD4_HUMAN
• Pfam ID: PF00046
• Sequence:
  MVMSSYMVNSKYVDPKFPPCEEYLQGGYLGEQGADYYGGGAQGADFQPPGLYPRPDFGEQ
  PFGGSGPGPGSALPARGHGQEPGGPGGHYAAPGEPCPAPPAPPPAPLPGARAYSQSDPKQ
  PPSGTALKQPAVVYPWMKKVHVNSVNPNYTGGEPKRSRTAYTRQQVLELEKEFHFNRYLT
  RRRRIEIAHTLCLSERQIKIWFQNRRMKWKKDHKLPNTKGRSSSSSSSSSCSSSVAPSQH
  LQPMAKDHHTDLTTL
• Function: Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Homeobox protein Hox-D4 (HOXD4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Homeobox protein Hox-D4 (HOXD4).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Homeobox protein Hox-D4 (HOXD4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein Hox-D4 (HOXD4).	[14]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-D4 (HOXD4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein Hox-D4 (HOXD4).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Homeobox protein Hox-D4 (HOXD4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-D4 (HOXD4).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Homeobox protein Hox-D4 (HOXD4).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Homeobox protein Hox-D4 (HOXD4).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Homeobox protein Hox-D4 (HOXD4).	[8]

References

• [1] Mutation analysis of the HOX paralogous 4-13 genes in children with acute lymphoid malignancies: identification of a novel germline mutation of HOXD4 leading to a partial loss-of-function.Hum Mutat. 2005 Apr;25(4):384-95. doi: 10.1002/humu.20155.
• [2] Clinicopathological analysis of HOXD4 expression in diffuse gliomas and its correlation with IDH mutations and 1p/19q co-deletion.Oncotarget. 2017 Dec 18;8(70):115657-115666. doi: 10.18632/oncotarget.23371. eCollection 2017 Dec 29.
• [3] High HOXD4 protein expression in gastric adenocarcinoma tissues indicates unfavorable clinical outcomes.Saudi J Gastroenterol. 2019 Jan-Feb;25(1):46-54. doi: 10.4103/sjg.SJG_105_18.
• [4] Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation.Tumour Biol. 1996;17(1):34-47. doi: 10.1159/000217965.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [11] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [12] 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.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.