Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0107817
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dc.titleThe KDM2B-let-7b-EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy
dc.contributor.authorKaroopongse E.
dc.contributor.authorYeung C.
dc.contributor.authorByon J.
dc.contributor.authorRamakrishnan A.
dc.contributor.authorHolman Z.J.
dc.contributor.authorJiang P.Y.Z.
dc.contributor.authorYu Q.
dc.contributor.authorDeeg H.J.
dc.contributor.authorMarcondes A.M.
dc.date.accessioned2019-11-07T05:07:23Z
dc.date.available2019-11-07T05:07:23Z
dc.date.issued2014
dc.identifier.citationKaroopongse E., Yeung C., Byon J., Ramakrishnan A., Holman Z.J., Jiang P.Y.Z., Yu Q., Deeg H.J., Marcondes A.M. (2014). The KDM2B-let-7b-EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy. PLoS ONE 9 (9) : e107817. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0107817
dc.identifier.issn19326203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/161772
dc.description.abstractBoth DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that dysregulated interactions of KDM2B, let-7b and EZH2 signals lead to an aberrant epigenetic landscape. Gene expression in CD34+ cells from MDS marrows was analyzed by NanoString miR array and validated by real-time polymerase chain reaction (PCR). The functions of KDM2B, let-7b and EZH2 were characterized in myeloid cell lines and in primary MDS cells. Let-7b levels were significantly higher, and KDM2B and EZH2 expression was lower in primary CD34+ MDS marrow cells (n = 44) than in healthy controls (n = 21; p<0.013, and p<0.0001, respectively). Overexpression of let-7b reduced EZH2 and KDM2B protein levels, and decreased cells in S-phase while increasing G0/G1 cells (p = 0.0005), accompanied by decreased H3K27me3 and cyclin D1. Silencing of KDM2B increased let-7b expression. Treatment with the cyclopentanyl analog of 3-deazaadenosine, DZNep, combined with the DNA hypomethylating agent 5-azacitidine, decreased levels of EZH2, suppressed methylation of di- and tri-methylated H3K27, and increased p16 expression, associated with cell proliferation. Thus, KDM2B, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed the inhibitory KDM2B/let-7b/EZH2 axis by preventing H3K27 methylation and reducing cell proliferation. DZNep might be able to enhance the therapeutic effects of DNA hypomethylating agents such as 5-azacitidine, currently considered standard therapy for patients with MDS. © PLOS ONE 2014.
dc.sourceUnpaywall 20191101
dc.subject3 deazaneplanocin A
dc.subjectazacitidine
dc.subjectcyclin D1
dc.subjecthistone demethylase
dc.subjectmicroRNA
dc.subjectmicroRNA let 7b
dc.subjectprotein KDM2B
dc.subjectprotein p16
dc.subjecttranscription factor EZH2
dc.subjectunclassified drug
dc.subjectazacitidine
dc.subjectEZH2 protein, human
dc.subjectF box protein
dc.subjecthistone
dc.subjecthistone demethylase
dc.subjectKDM2A protein, human
dc.subjectmicroRNA
dc.subjectmirnlet7 microRNA, human
dc.subjectpolycomb repressive complex 2
dc.subjectArticle
dc.subjectbone marrow culture
dc.subjectCD34 selection
dc.subjectcell cycle G0 phase
dc.subjectcell cycle G1 phase
dc.subjectcell cycle S phase
dc.subjectcell proliferation
dc.subjectcontrolled study
dc.subjectDNA methylation
dc.subjectepigenetics
dc.subjectgene overexpression
dc.subjectgene repression
dc.subjectgene silencing
dc.subjectgenetic transcription
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthuman tissue
dc.subjectmyelodysplastic syndrome
dc.subjectprotein blood level
dc.subjectprotein expression
dc.subjectprotein function
dc.subjectreal time polymerase chain reaction
dc.subjectbone marrow cell
dc.subjectcluster analysis
dc.subjectdrug effects
dc.subjectgene expression
dc.subjectgene expression profiling
dc.subjectgenetic epigenesis
dc.subjectgenetics
dc.subjectmetabolism
dc.subjectmethylation
dc.subjectmolecularly targeted therapy
dc.subjectMyelodysplastic Syndromes
dc.subjectpathology
dc.subjecttumor cell line
dc.subjectAzacitidine
dc.subjectBone Marrow Cells
dc.subjectCell Line, Tumor
dc.subjectCluster Analysis
dc.subjectEpigenesis, Genetic
dc.subjectF-Box Proteins
dc.subjectGene Expression
dc.subjectGene Expression Profiling
dc.subjectGene Knockdown Techniques
dc.subjectHistones
dc.subjectHumans
dc.subjectJumonji Domain-Containing Histone Demethylases
dc.subjectMethylation
dc.subjectMicroRNAs
dc.subjectMolecular Targeted Therapy
dc.subjectMyelodysplastic Syndromes
dc.subjectPolycomb Repressive Complex 2
dc.typeArticle
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.description.doi10.1371/journal.pone.0107817
dc.description.sourcetitlePLoS ONE
dc.description.volume9
dc.description.issue9
dc.description.pagee107817
dc.published.statePublished
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