Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT52VJ6V)

• DOT Name: Homeobox protein Hox-C4 (HOXC4)
• Synonyms: Homeobox protein CP19; Homeobox protein Hox-3E
• Gene Name: HOXC4
• Related Disease:
  HER2/NEU overexpressing breast cancer
  Actinic keratosis
  Acute myelogenous leukaemia
  Adrenocortical carcinoma
  Cardiovascular disease
  Glioma
  Hydatidiform mole
  Leukemia
  Myeloid leukaemia
  Neoplasm
  Skin neoplasm
  Type-1/2 diabetes
• UniProt ID: HXC4_HUMAN
• Pfam ID: PF00046
• Sequence:
  MIMSSYLMDSNYIDPKFPPCEEYSQNSYIPEHSPEYYGRTRESGFQHHHQELYPPPPPRP
  SYPERQYSCTSLQGPGNSRGHGPAQAGHHHPEKSQSLCEPAPLSGASASPSPAPPACSQP
  APDHPSSAASKQPIVYPWMKKIHVSTVNPNYNGGEPKRSRTAYTRQQVLELEKEFHYNRY
  LTRRRRIEIAHSLCLSERQIKIWFQNRRMKWKKDHRLPNTKVRSAPPAGAAPSTLSAATP
  GTSEDHSQSATPPEQQRAEDITRL
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
HER2/NEU overexpressing breast cancer	DISYKID5	Definitive	Biomarker	[1]
Actinic keratosis	DISR1RC5	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hydatidiform mole	DISKNP7O	Strong	Altered Expression	[7]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Skin neoplasm	DIS16DDV	Strong	Altered Expression	[2]
Type-1/2 diabetes	DISIUHAP	Disputed	Altered Expression	[8]

2 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-C4 (HOXC4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Homeobox protein Hox-C4 (HOXC4).	[15]

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-C4 (HOXC4).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein Hox-C4 (HOXC4).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-C4 (HOXC4).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Homeobox protein Hox-C4 (HOXC4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Homeobox protein Hox-C4 (HOXC4).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Homeobox protein Hox-C4 (HOXC4).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Homeobox protein Hox-C4 (HOXC4).	[17]

References

• [1] Identification of key genes involved in HER2-positive breast cancer.Eur Rev Med Pharmacol Sci. 2016;20(4):664-72.
• [2] Expression of the homeobox gene HOXC4 in keratinocytes of normal skin and epithelial skin tumors is correlated with differentiation.J Invest Dermatol. 1994 Sep;103(3):341-6. doi: 10.1111/1523-1747.ep12394888.
• [3] Differentiation and cell-type-restricted expression of HOXC4, HOXC5 and HOXC6 in myeloid leukemias and normal myeloid cells.Leukemia. 1998 Nov;12(11):1724-32. doi: 10.1038/sj.leu.2401106.
• [4] Complex karyotype in a childhood adrenocortical carcinoma.Cancer Genet Cytogenet. 1998 Sep;105(2):190-2. doi: 10.1016/s0165-4608(98)00018-1.
• [5] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [6] CD133 in brain tumor: the prognostic factor.Oncotarget. 2017 Feb 14;8(7):11144-11159. doi: 10.18632/oncotarget.14406.
• [7] The three most downstream genes of the Hox-3 cluster are expressed in human extraembryonic tissues including trophoblast of androgenetic origin.Development. 1990 Mar;108(3):471-7. doi: 10.1242/dev.108.3.471.
• [8] Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution.Cell Physiol Biochem. 2018;45(5):1999-2008. doi: 10.1159/000487976. Epub 2018 Mar 2.
• [9] 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.
• [10] 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.
• [11] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [15] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [16] 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.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.