Abstract
Histone H3 lysine 27 tri-methylation (H3K27me3) -dependent transcription regulation is a fundamental process of gene control. Although EZH2 mutation is observed in certain lymphoma types, many other cancers show global H3K27me3 accumulation irrespective of mutation. However, the underlying mechanisms of gene silencing and therapeutic efficacies of epigenetic drugs remain unclear. In this study, we showed that globally-accumulated H3K27me3 is induced by both cis-bound EZH1 and EZH2 in mature lymphocyte-derived malignancies. Mutual interference and compensatory functions of co-expressed EZH1/2 rearrange the genome-wide distribution, establishing restricted chromatin and gene expression signatures. Using novel EZH1/2 dual inhibitors, we found that both EZH1 and EZH2 are required for the maintenance and induction of H3K27me3. The synthetic lethality of targeting EZH1 and EZH2 was observed in lymphoma models and primary adult T-cell leukemia/lymphoma (ATL) cells harboring H3K27me3 accumulation. This heritable EZH1/2 dysfunctional state was epigenetically imprinted at the virus-infected, immortalized phase. EZH1/2 dual inhibition could eliminate infected cell populations more effectively than EZH2 inhibition. Regarding the frequent observation of H3K27me3 accumulation in advanced-stage and early-phase malignant progenitors, the emerging EZH1- and EZH2-dependent epigenetic reprograming is an incipient process of fate decision within developmental pathways of cancers.
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