Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6G6ZIK)

• DOT Name: Homeobox protein Hox-A2 (HOXA2)
• Synonyms: Homeobox protein Hox-1K
• Gene Name: HOXA2
• Related Disease:
  Acute myelogenous leukaemia
  Bilateral microtia-deafness-cleft palate syndrome
  Cleft palate
  Colorectal carcinoma
  Cystic fibrosis
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Isolated cleft palate
  Neoplasm
  Squamous cell carcinoma
  Ear malformation
  Nasopharyngeal carcinoma
  Microtia
• UniProt ID: HXA2_HUMAN
• Pfam ID: PF00046
• Sequence:
  MNYEFEREIGFINSQPSLAECLTSFPPVADTFQSSSIKTSTLSHSTLIPPPFEQTIPSLN
  PGSHPRHGAGGRPKPSPAGSRGSPVPAGALQPPEYPWMKEKKAAKKTALLPAAAAAATAA
  ATGPACLSHKESLEIADGSGGGSRRLRTAYTNTQLLELEKEFHFNKYLCRPRRVEIAALL
  DLTERQVKVWFQNRRMKHKRQTQCKENQNSEGKCKSLEDSEKVEEDEEEKTLFEQALSVS
  GALLEREGYTFQQNALSQQQAPNGHNGDSQSFPVSPLTSNEKNLKHFQHQSPTVPNCLST
  MGQNCGAGLNNDSPEALEVPSLQDFSVFSTDSCLQLSDAVSPSLPGSLDSPVDISADSLD
  FFTDTLTTIDLQHLNY
• 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:
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Bilateral microtia-deafness-cleft palate syndrome	DISVBDJ9	Strong	Autosomal dominant	[2]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[6]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[6]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[8]
Ear malformation	DISVJGPS	moderate	Genetic Variation	[9]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[7]
Microtia	DISB3GQC	Supportive	Autosomal dominant	[2]

6 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-A2 (HOXA2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein Hox-A2 (HOXA2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-A2 (HOXA2).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Homeobox protein Hox-A2 (HOXA2).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Homeobox protein Hox-A2 (HOXA2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Hox-A2 (HOXA2).	[16]

2 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 affects the methylation of Homeobox protein Hox-A2 (HOXA2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein Hox-A2 (HOXA2).	[17]

References

• [1] The Role of the HOXA Gene Family in Acute Myeloid Leukemia.Genes (Basel). 2019 Aug 16;10(8):621. doi: 10.3390/genes10080621.
• [2] HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss. Hum Mutat. 2013 Oct;34(10):1347-51. doi: 10.1002/humu.22367. Epub 2013 Jul 11.
• [3] Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non-syndromic microtia and distinctive ear morphology.Clin Genet. 2017 May;91(5):774-779. doi: 10.1111/cge.12845. Epub 2016 Sep 13.
• [4] Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and Its Clinicopathological Characteristics in Colorectal Cancer.Front Oncol. 2019 May 21;9:394. doi: 10.3389/fonc.2019.00394. eCollection 2019.
• [5] The little (lit) mutation cosegregates with the growth hormone releasing factor receptor on mouse chromosome 6.Mamm Genome. 1993;4(10):555-9. doi: 10.1007/BF00361384.
• [6] Quantitative expression of the homeobox and integrin genes in human gastric carcinoma.Int J Mol Med. 2007 Oct;20(4):621-9.
• [7] Aberrantly hypermethylated Homeobox A2 derepresses metalloproteinase-9 through TBP and promotes invasion in Nasopharyngeal carcinoma.Oncotarget. 2013 Nov;4(11):2154-65. doi: 10.18632/oncotarget.1367.
• [8] A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis.Int J Cancer. 2020 Jan 15;146(2):388-399. doi: 10.1002/ijc.32532. Epub 2019 Jul 8.
• [9] Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome.Am J Med Genet A. 2009 May;149A(5):837-43. doi: 10.1002/ajmg.a.32747.
• [10] Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster. RNA. 2007 Feb;13(2):223-39. doi: 10.1261/rna.266707. Epub 2006 Dec 21.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [15] 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.
• [16] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [17] 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.