KDM3B Is the H3K9 Demethylase Involved in Transcriptional Activation of lmo2 in Leukemia

Abstract

f Histone lysine methylation and demethylation are considered critical steps in transcriptional regulation. In this report, we performed chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis to examine the genome-wide occupancy of H3K9-me2 during all-trans-retinoic acid (ATRA)-induced differentiation of HL-60 promyelocytic leukemia cells. Using this approach, we found that KDM3B, which contains a JmjC domain, was downregulated during differentiation through the recruitment of a corepressor complex. Furthermore, KDM3B displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene lmo2 expression via a synergistic interaction with CBP. Here, we found that KDM3B repressed leukemia cell differentiation and was upregulated in blood cells from acute lymphoblastic leukemia (ALL)-type leukemia patients. The combined results of this study provide evidence that the H3K9-me1/2 demethylase KDM3B might play a role in leukemogenesis via activation of lmo2 through interdependent actions with the histone acetyltransferase (HAT) complex containing CBP.

Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling

“…KDM3B was recently characterized as a member of the JumonjiC domain-containing histone demethylases that shows specificity toward H3K9 and is involved gene activation in leukemia cells [25, 26], however, a role for this factor in PEV has not been reported. To test whether increased recruitment of KDM3B by H3K9M nucleosomes might result in decreased H3K9-methylation, we knocked down or over-expressed its Drosophila homolog, JHDM2, in wing imaginal discs.…”

Expression pattern of JMJD1C in oocytes and its impact on early embryonic development

“…All the JMJD1 family members contain the JMJC domain and are capable of specifically removing H3K9me1 and H3K9me2 methylation modifications but not H3K9me3 (Okada et al, 2007;Kim et al, 2010;Kim et al, 2012). It is now generally accepted that JMJD1C is the third member of the KDM3 family, i.e., KDM3C.…”

“…JMJD1C can specifically prevent H3K9me1 and H3K9me2 methylation, and has no catalytic effect on H3K9me3 (Okada et al, 2007;Kim et al, 2010;Kim et al, 2012). Studies have shown that the promoter region of JMJD1C gene has POU5F1/OCT-4 binding sites.…”

The Jumonji family: past, present and future of histone demethylases in cancer

“…In addition, KDM3B suppressed differentiation of leukaemia cells, and was up-regulated in acute lymphoblastic leukaemia (ALL) patients. KDM3B might therefore play a key role in leukaemogenesis, although more studies are needed to support this preliminary hypothesis (86). Another statistical study conducted in breast cancer reported that overexpression of KDM3B/KDM5A and KDM6A is associated with improved and poor prognosis, respectively.…”

“…Another statistical study conducted in breast cancer reported that overexpression of KDM3B/KDM5A and KDM6A is associated with improved and poor prognosis, respectively. Although these finding require further investigation, they suggest that rebalancing protein methylation levels might represent a new avenue for cancer therapy (86). JMJD1C has been proposed as an AR co-activator (87).…”