Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKZA25M)

• DOT Name: CCAAT/enhancer-binding protein epsilon (CEBPE)
• Synonyms: C/EBP epsilon
• Gene Name: CEBPE
• Related Disease:
  Hepatocellular carcinoma
  Acute leukaemia
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Acute myocardial infarction
  Advanced cancer
  Atrichia with papular lesions
  Myelodysplastic syndrome
  Neoplasm
  Progressive multifocal leukoencephalopathy
  Specific granule deficiency 1
  Specific granule deficiency 2
  Bacterial infection
  Specific granule deficiency
  Childhood acute lymphoblastic leukemia
  leukaemia
  Leukemia
  T-cell leukaemia
• UniProt ID: CEBPE_HUMAN
• PDB ID: 3T92
• Pfam ID: PF07716
• Sequence:
  MSHGTYYECEPRGGQQPLEFSGGRAGPGELGDMCEHEASIDLSAYIESGEEQLLSDLFAV
  KPAPEARGLKGPGTPAFPHYLPPDPRPFAYPPHTFGPDRKALGPGIYSSPGSYDPRAVAV
  KEEPRGPEGSRAASRGSYNPLQYQVAHCGQTAMHLPPTLAAPGQPLRVLKAPLATAAPPC
  SPLLKAPSPAGPLHKGKKAVNKDSLEYRLRRERNNIAVRKSRDKAKRRILETQQKVLEYM
  AENERLRSRVEQLTQELDTLRNLFRQIPEAANLIKGVGGCS
• Function: Transcriptional activator. C/EBP are DNA-binding proteins that recognize two different motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers. Required for the promyelocyte-myelocyte transition in myeloid differentiation.
• Tissue Specificity: Strongest expression occurs in promyelocyte and late-myeloblast-like cell lines.
• KEGG Pathway:
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway: Transcriptional regulation of granulopoiesis (R-HSA-9616222)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[6]
Atrichia with papular lesions	DIS80CUB	Strong	Biomarker	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[8]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Altered Expression	[9]
Specific granule deficiency 1	DISL32CF	Strong	Autosomal recessive	[10]
Specific granule deficiency 2	DIS4H1XW	Strong	GermlineCausalMutation	[11]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[12]
Specific granule deficiency	DISXJ6Y2	Supportive	Autosomal recessive	[11]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[3]
leukaemia	DISS7D1V	Limited	Biomarker	[6]
Leukemia	DISNAKFL	Limited	Biomarker	[6]
T-cell leukaemia	DISJ6YIF	Limited	Genetic Variation	[13]

9 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 CCAAT/enhancer-binding protein epsilon (CEBPE).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[16]
Pomalidomide	DMTGBAX	Approved	Pomalidomide increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[22]
Caffeic acid phenethyl ester	DMRJKIV	Investigative	Caffeic acid phenethyl ester increases the expression of CCAAT/enhancer-binding protein epsilon (CEBPE).	[23]

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 CCAAT/enhancer-binding protein epsilon (CEBPE).	[19]

References

• [1] C-reactive protein is an independent predictor for hepatocellular carcinoma recurrence after liver transplantation.PLoS One. 2019 May 29;14(5):e0216677. doi: 10.1371/journal.pone.0216677. eCollection 2019.
• [2] Association between CEBPE Variant and Childhood Acute Leukemia Risk: Evidence from a Meta-Analysis of 22 Studies.PLoS One. 2015 May 4;10(5):e0125657. doi: 10.1371/journal.pone.0125657. eCollection 2015.
• [3] Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.Blood. 2019 Oct 10;134(15):1227-1237. doi: 10.1182/blood.2018890764.
• [4] CEBPE expression is an independent prognostic factor for acute myeloid leukemia.J Transl Med. 2019 Jun 4;17(1):188. doi: 10.1186/s12967-019-1944-x.
• [5] Selenoprotein P in Myocardial Infarction With Cardiogenic Shock.Shock. 2020 Jan;53(1):58-62. doi: 10.1097/SHK.0000000000001342.
• [6] Association of genetic variation in IKZF1, ARID5B, CDKN2A, and CEBPE with the risk of acute lymphoblastic leukemia in Tunisian children and their contribution to racial differences in leukemia incidence.Pediatr Hematol Oncol. 2016 Apr;33(3):157-67. doi: 10.3109/08880018.2016.1161685.
• [7] Activation of G0S2 is coordinated by recruitment of PML/RAR and C/EBP to its promoter during ATRA-induced APL differentiation.J Leukoc Biol. 2017 Mar;101(3):655-664. doi: 10.1189/jlb.1A0316-116R. Epub 2016 Sep 7.
• [8] C/EBP-epsilon: chromosomal mapping and mutational analysis of the gene in leukemia and preleukemia.Leuk Res. 1997 Sep;21(9):833-9. doi: 10.1016/s0145-2126(97)00072-6.
• [9] PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms.J Cell Biochem. 2019 Feb;120(2):1210-1220. doi: 10.1002/jcb.27077. Epub 2018 Oct 18.
• [10] CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge. Blood. 1999 May 1;93(9):3096-105.
• [11] Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon. J Exp Med. 1999 Jun 7;189(11):1847-52. doi: 10.1084/jem.189.11.1847.
• [12] Neutralization of viral infectivity by zebrafish c-reactive protein isoforms.Mol Immunol. 2017 Nov;91:145-155. doi: 10.1016/j.molimm.2017.09.005. Epub 2017 Sep 12.
• [13] Translocation (14;14)(q11;q32) with simultaneous involvement of the IGH and CEBPE genes in B-lineage acute lymphoblastic leukemia.Cancer Genet Cytogenet. 2008 Dec;187(2):125-9. doi: 10.1016/j.cancergencyto.2008.08.008.
• [14] Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia. Blood. 2002 Aug 1;100(3):1008-13. doi: 10.1182/blood.v100.3.1008.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [18] Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and?mortality. EMBO Mol Med. 2016 Nov 2;8(11):1340-1359. doi: 10.15252/emmm.201606434. Print 2016 Nov.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [22] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [23] Enhancement of caffeic acid phenethyl ester on all-trans retinoic acid-induced differentiation in human leukemia HL-60 cells. Toxicol Appl Pharmacol. 2006 Oct 1;216(1):80-8. doi: 10.1016/j.taap.2006.04.007.