Yan J1, Li B2, Lin B3, Lee PT1, Chung TH1, Tan J1, Bi C1, Lee XT1, Selvarajan V4, Ng SB4, Yang H1, Yu Q5, Chng WJ6
1Cancer Science Institute of Singapore, National University of Singapore, Singapore;
2Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
3Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore;
4Department of Pathology, National University Health System, Singapore;
5Department of Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
6Cancer Science Institute of Singapore, National University of Singapore, Singapore; email@example.com
The best-understood mechanism by which EZH2 exerts its oncogenic function is through PRC2-mediated gene repression, which requires its histone methyltransferase activity. However small-molecule inhibitors of EZH2 that selectively targets its enzymatic activity turn out to be potent only for lymphoma cells with EZH2-activating mutation. Intriguingly, recent discoveries, including ours, have placed EZH2 into the category of transcriptional co-activators and thus raised the possibility of non-canonical signaling pathways. However, it remains unclear how EZH2 switches to this catalytic independent function. In the current study, using natural killer / T-cell lymphoma (NKTL) as a disease model, we found that phosphorylation of EZH2 by JAK3 promotes the dissociation of the PRC2 complex leading to decreased global H3K27me3 levels, while it switches EZH2 to a transcriptional activator, conferring higher proliferative capacity of the affected cells. Gene expression data analysis also suggests that the non-canonical function of EZH2 as a transcriptional activator up-regulates a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness and invasiveness. Consistently, JAK3 inhibitor was able to significantly reduce the growth of NKTL cells, in a EZH2 phosphorylation-dependent manner, whereas various compounds recently developed to inhibit EZH2 methyltransferase activity have no such effect. Thus pharmacological inhibition of JAK3 activity may provide a promising treatment option for NKTL through the novel mechanism of suppressing non-canonical EZH2 activity.