Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJPKMX4)

• DOT Name: Hemoglobin subunit epsilon (HBE1)
• Synonyms: Epsilon-globin; Hemoglobin epsilon chain
• Gene Name: HBE1
• Related Disease:
  Advanced cancer
  Beta thalassemia
  Congenital anemia
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung carcinoma
  Lung squamous cell carcinoma
  Malaria
  Melorheostosis
  Non-small-cell lung cancer
  Plasmodium falciparum malaria
  Sickle-cell anaemia
  Acute erythroid leukemia
  Chronic obstructive pulmonary disease
  Small-cell lung cancer
  Adenocarcinoma
• UniProt ID: HBE_HUMAN
• PDB ID: 1A9W
• Pfam ID: PF00042
• Sequence:
  MVHFTAEEKAAVTSLWSKMNVEEAGGEALGRLLVVYPWTQRFFDSFGNLSSPSAILGNPK
  VKAHGKKVLTSFGDAIKNMDNLKPAFAKLSELHCDKLHVDPENFKLLGNVMVIILATHFG
  KEFTPEVQAAWQKLVSAVAIALAHKYH
• Function: The epsilon chain is a beta-type chain of early mammalian embryonic hemoglobin.
• Tissue Specificity: Red blood cells.
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Beta thalassemia	DIS5RCQK	Strong	Altered Expression	[2]
Congenital anemia	DISTW0J6	Strong	Biomarker	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[6]
Malaria	DISQ9Y50	Strong	Genetic Variation	[8]
Melorheostosis	DISIMCL3	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Plasmodium falciparum malaria	DIS3Q9KF	Strong	Biomarker	[11]
Sickle-cell anaemia	DIS5YNZB	Strong	Genetic Variation	[12]
Acute erythroid leukemia	DISZFC1O	moderate	Altered Expression	[13]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[14]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[15]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[16]

10 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 Hemoglobin subunit epsilon (HBE1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hemoglobin subunit epsilon (HBE1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hemoglobin subunit epsilon (HBE1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hemoglobin subunit epsilon (HBE1).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Hemoglobin subunit epsilon (HBE1).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Hemoglobin subunit epsilon (HBE1).	[22]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Hemoglobin subunit epsilon (HBE1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Hemoglobin subunit epsilon (HBE1).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Hemoglobin subunit epsilon (HBE1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Hemoglobin subunit epsilon (HBE1).	[26]

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 Hemoglobin subunit epsilon (HBE1).	[25]

References

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• [2] Dynamic posttranscriptional regulation of epsilon-globin gene expression in vivo.Blood. 2007 Jan 15;109(2):795-801. doi: 10.1182/blood-2006-06-027946. Epub 2006 Sep 26.
• [3] Expression of embryonic zeta-globin and epsilon-globin chains in a 10-year-old girl with congenital anemia.Blood. 1993 Mar 15;81(6):1636-40.
• [4] Evidence for a base-paired region of hepatitis B virus pregenome encapsidation signal which influences the patterns of precore mutations abolishing HBe protein expression.J Virol. 1993 Sep;67(9):5651-5. doi: 10.1128/JVI.67.9.5651-5655.1993.
• [5] The role of c-Jun phosphorylation in EpRE activation of phase II genes.Free Radic Biol Med. 2009 Oct 15;47(8):1172-9. doi: 10.1016/j.freeradbiomed.2009.07.036. Epub 2009 Aug 7.
• [6] Methylation of PRDM2, PRDM5 and PRDM16 genes in lung cancer cells.Int J Clin Exp Pathol. 2014 Apr 15;7(5):2305-11. eCollection 2014.
• [7] Expression and regulation of a molecular marker, SPR1, in multistep bronchial carcinogenesis.Am J Respir Cell Mol Biol. 2000 Jan;22(1):92-6. doi: 10.1165/ajrcmb.22.1.3637.
• [8] Genome-wide association study indicates two novel resistance loci for severe malaria.Nature. 2012 Sep 20;489(7416):443-6. doi: 10.1038/nature11334. Epub 2012 Aug 15.
• [9] Tissue specific transcription of the human epsilon-globin gene following transfection into the embryonic erythroid cell line K562.Nucleic Acids Res. 1985 Sep 11;13(17):6125-36. doi: 10.1093/nar/13.17.6125.
• [10] A novel pathway in NSCLC cells: miR?91, targeting NFIA, is induced by chronic hypoxia, and promotes cell proliferation and migration.Mol Med Rep. 2017 Mar;15(3):1319-1325. doi: 10.3892/mmr.2017.6100. Epub 2017 Jan 4.
• [11] Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection.Am J Hum Genet. 2004 Jun;74(6):1198-208. doi: 10.1086/421330. Epub 2004 Apr 27.
• [12] Genetic determinants of haemolysis in sickle cell anaemia.Br J Haematol. 2013 Apr;161(2):270-8. doi: 10.1111/bjh.12245. Epub 2013 Feb 14.
• [13] Non-coding transcripts far upstream of the epsilon-globin gene are distinctly expressed in human primary tissues and erythroleukemia cell lines.Biochem Biophys Res Commun. 2006 Jun 2;344(2):623-30. doi: 10.1016/j.bbrc.2006.03.189. Epub 2006 Apr 6.
• [14] Increased expression of heat shock protein 70 in chronic obstructive pulmonary disease.Int Immunopharmacol. 2013 Nov;17(3):885-93. doi: 10.1016/j.intimp.2013.09.003. Epub 2013 Oct 3.
• [15] Quantitative proteomic analysis of mitochondrial proteins differentially expressed between small cell lung cancer cells and normal human bronchial epithelial cells.Thorac Cancer. 2018 Nov;9(11):1366-1375. doi: 10.1111/1759-7714.12839. Epub 2018 Sep 9.
• [16] Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis.Eur Respir J. 2012 May;39(5):1171-80. doi: 10.1183/09031936.00184410. Epub 2011 Sep 29.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] 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.
• [19] 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.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [23] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [24] 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.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.