The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma.
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.
School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
J A
JA
Anderton
S
S
Bose
M
M
Vockerodt
K
K
Vrzalikova
W
W
Wei
M
M
Kuo
K
K
Helin
J
J
Christensen
M
M
Rowe
P G
PG
Murray
C B
CB
Woodman
D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006689:Hodgkin Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human