Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0107817
Title: The KDM2B-let-7b-EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy
Authors: Karoopongse E.
Yeung C.
Byon J.
Ramakrishnan A.
Holman Z.J.
Jiang P.Y.Z.
Yu Q. 
Deeg H.J.
Marcondes A.M.
Keywords: 3 deazaneplanocin A
azacitidine
cyclin D1
histone demethylase
microRNA
microRNA let 7b
protein KDM2B
protein p16
transcription factor EZH2
unclassified drug
azacitidine
EZH2 protein, human
F box protein
histone
histone demethylase
KDM2A protein, human
microRNA
mirnlet7 microRNA, human
polycomb repressive complex 2
Article
bone marrow culture
CD34 selection
cell cycle G0 phase
cell cycle G1 phase
cell cycle S phase
cell proliferation
controlled study
DNA methylation
epigenetics
gene overexpression
gene repression
gene silencing
genetic transcription
human
human cell
human tissue
myelodysplastic syndrome
protein blood level
protein expression
protein function
real time polymerase chain reaction
bone marrow cell
cluster analysis
drug effects
gene expression
gene expression profiling
genetic epigenesis
genetics
metabolism
methylation
molecularly targeted therapy
Myelodysplastic Syndromes
pathology
tumor cell line
Azacitidine
Bone Marrow Cells
Cell Line, Tumor
Cluster Analysis
Epigenesis, Genetic
F-Box Proteins
Gene Expression
Gene Expression Profiling
Gene Knockdown Techniques
Histones
Humans
Jumonji Domain-Containing Histone Demethylases
Methylation
MicroRNAs
Molecular Targeted Therapy
Myelodysplastic Syndromes
Polycomb Repressive Complex 2
Issue Date: 2014
Citation: Karoopongse 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
Abstract: Both 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.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161772
ISSN: 19326203
DOI: 10.1371/journal.pone.0107817
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