The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma

School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
Oncogene (Impact Factor: 8.46). 01/2011; 30(17):2037-43. DOI: 10.1038/onc.2010.579
Source: PubMed


There is now evidence for both increased and decreased activity of the enzymes controlling the methylation of lysine 27 on histone 3 (H3K27) in cancer. One of these enzymes, KDM6B formally known as JMJD3, a histone demethylase, which removes the trimethyl mark from H3K27, is required for the lineage commitment and terminal differentiation of neural stem cells and of keratinocytes. Our results suggest that KDM6B may also have a role in antigen-driven B-cell differentiation. KDM6B expression increases in B-cell subsets with increasing stage of differentiation, and gene expression profiling shows that KDM6B transcriptional targets in germinal centre B (GC B) cells are significantly enriched for those differentially expressed during memory and plasma cell differentiation. Our results also suggest that aberrant expression of KDM6B may contribute to the pathogenesis of Hodgkin's Lymphoma (HL), an Epstein-Barr virus (EBV) associated malignancy. KDM6B is over-expressed in primary HL and induced by the EBV oncogene, latent membrane protein (LMP1) in GC B cells, the presumptive progenitors of HL. Consistent with these observations, we found that KDM6B transcriptional targets in GC B cells are enriched for genes differentially expressed in HL, and that KDM6B depletion can restore the tri-methylation of H3K27 on these genes.

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Available from: Martina Vockerodt, Apr 03, 2014
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    • "Recent evidence has shown that increased and decreased activity of enzymes controlling H3K27me3 contributes to carcinogenesis. This includes both EZH2 (26), KDM6B/JMJD3 (25) and UTX. For instance, JMJD3 (the main H3K27me3 demethylase) has been reported to be induced by EBV (25). "
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    ABSTRACT: Epstein-Barr virus (EBV) infects and transforms human primary B cells inducing indefinite proliferation. To investigate the potential participation of chromatin mechanisms during the EBV-mediated transformation of resting B cells we performed an analysis of global changes in histone modifications. We observed a remarkable decrease and redistribution of heterochromatin marks including H4K20me3, H3K27me3 and H3K9me3. Loss of H4K20me3 and H3K9me3 occurred at constitutive heterochromatin repeats. For H3K27me3 and H3K9me3, comparison of ChIP-seq data revealed a decrease in these marks in thousands of genes, including clusters of HOX and ZNF genes, respectively. Moreover, DNase-seq data comparison between resting and EBV-transformed B cells revealed increased endonuclease accessibility in thousands of genomic sites. We observed that both loss of H3K27me3 and increased accessibility are associated with transcriptional activation. These changes only occurred in B cells transformed with EBV and not in those stimulated to proliferate with CD40L/IL-4, despite their similarities in the cell pathways involved and proliferation rates. In fact, B cells infected with EBNA-2 deficient EBV, which have much lower proliferation rates, displayed similar decreases for heterochromatic histone marks. Our study describes a novel phenomenon related to transformation of B cells, and highlights its independence of the pure acquisition of proliferation.
    Full-text · Article · Oct 2013 · Nucleic Acids Research
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    • "This study also demonstrated that upregulated expression of the H3K27 demethylases UTX and JMJD3 was relevant to tumor suppression. Previous studies found evidence for JMJD3 regulation in tissues from many cancers, including prostate cancer and primary Hodgkin’s lymphoma [20,37]. Further studies of the relationship between histone demethylases and cancer development will improve our understanding of the molecular mechanisms involved, and potentially aid in the development of new therapies for RCC [43,44]. "
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    ABSTRACT: Background The histone H3K27 demethylases UTX and JMJD3 are important regulatory factors that modulate gene expression by altering the physical state of chromatin. Previous studies have indicated an abnormal H3K27 methylation status in carcinogenesis. We therefore investigated the expression patterns of UTX and JMJD3 in renal cell carcinoma (RCC) and their roles in cancer development. Methods The mRNA expression levels of the UTX and JMJD3 genes were determined in cancer tissues and adjacent normal tissues in 36 patients with primary RCC, using quantitative real-time-polymerase chain reaction. The UTX and JMJD3 protein contents were measured by western blotting and immunohistochemical analysis. Results UTX and JMJD3 transcripts were significantly increased in cancer tissues compared to normal tissues (P < 0.05). mRNA levels of the inhibitor of cyclin-dependent kinases 4 and 6 p16INK4a were also increased in cancer tissues (P < 0.001). Western blotting indicated that levels of both demethylases were increased in cancer tissues. The level of tri-methylated H3K27 (H3K27me3) was lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 was increased (P < 0.05). These results suggest that the two H3K27 demethylases may play critical roles in the regulation of H3K27 methylation status in RCC. Immunohistochemical analysis confirmed that UTX and JMJD3 expression were upregulated in cancer tissues compared to adjacent tissues. Conclusions This study demonstrated that UTX and JMJD3 were upregulated in cancer tissues, suggesting that they may be involved in the development of primary RCC. The potential roles of H3K27 demethylases as biomarkers in the early diagnosis of RCC need to be further explored.
    Full-text · Article · Oct 2012 · BMC Cancer
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    • "Because of the redundant activity of EZH1 and EZH2 (Shen et al. 2009; Ezhkova et al. 2011; Mochizuki-Kashio et al. 2011), interference with both enzymes may prove synergistic. JMJD3 was found to be overexpressed in cases of Hodgkin's lymphoma and T-ALL and is associated with the loss of H3K27me3 at derepressed target genes that may contribute to pathogenesis (Anderton et al. 2011; Simon et al. 2012). Finally, depletion of UTX was recently reported to severely impair proliferation of human leukemia cell lines (Liu et al. 2012). "
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    ABSTRACT: In the April 1, 2012, issue of Genes & Development, Simon and colleagues (pp. 651-656) demonstrated that the disruption of Ezh2 in mice is sufficient to cause T-acute lymphoblastic leukemia (T-ALL). Moreover, in concert with concurrent studies, the authors revealed that similar mechanisms are involved in human T-ALL. These data contrast with previous findings showing that increased EZH2 activity promotes cancer.
    Preview · Article · Apr 2012 · Genes & development
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