Abstract
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased invitro and invivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.
Highlights
Epigenetic regulation of gene expression encompasses a variety of mechanisms that control gene activity by modifying chromatin without perturbing DNA sequence
Loss of UTX Promotes the Proliferation, Clonogenicity, and Adhesion of MM Cells To model in vitro the loss of UTX in MM, we used a pair of cell lines derived from the same MM patient (Hardin et al, 1994; Ridley et al, 1993): ARP-1 is UTX wild-type, while ARD harbors an homozygous deletion encompassing the UTX locus, as determined by comparative genomic hybridization (CGH) and mRNA sequencing
630 Cell Reports 21, 628–640, October 17, 2017 karyotyping and array-based CGH, detected some other differences between the cell lines, the most important being the stepwise rearrangement from Xp at the point of UTX loss in ARD (Xp/18q/1q) (Allen et al, 2013, Cancer Res., abstract)
Summary
Epigenetic regulation of gene expression encompasses a variety of mechanisms that control gene activity by modifying chromatin without perturbing DNA sequence. Alteration of methylation of lysine 27 on histone H3 (H3K27me) is a recurrent theme resulting from mutations in epigenetic regulators (Ezponda and Licht, 2014). Trimethylation of H3K27 (H3K27me3) is a repressive chromatin mark placed by the polycomb repressive complex 2 (PRC2), catalyzed by its central component EZH2, and removed by the histone demethylases UTX/KDM6A and JMJD3/KDM6B. Alterations in cancer include both gains and losses of the levels of H3K27me, underscoring the importance of a tightly regulated balance for cell homeostasis. Alterations of H3K27me are due to mutations in chromatin writers (EZH2 and other PRC2 components), erasers (UTX loss), alteration of other chromatin marks (MMSET overexpression), or mutation of the histone H3 itself (Ezponda and Licht, 2014)
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