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

TY - JOUR

T1 - The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma

AU - Anderton, J A

AU - Bose, S

AU - Vockerodt, M

AU - Vrzalikova, K

AU - Wei, W

AU - Kuo, M

AU - Helin, K

AU - Christensen, Jesper Aagaard

AU - Rowe, M

AU - Murray, P G

AU - Woodman, C B

PY - 2011/4/28

Y1 - 2011/4/28

N2 - 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.

AB - 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.

KW - B-Lymphocyte Subsets

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Cell Transformation, Viral

KW - Gene Expression Regulation, Neoplastic

KW - Herpesvirus 4, Human

KW - Hodgkin Disease

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases

KW - Transcription, Genetic

KW - Up-Regulation

KW - Viral Matrix Proteins

U2 - 10.1038/onc.2010.579

DO - 10.1038/onc.2010.579

M3 - Journal article

C2 - 21242977

SN - 0950-9232

VL - 30

SP - 2037

EP - 2043

JO - Oncogene

JF - Oncogene

IS - 17

ER -