EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma.
The best-understood mechanism by which EZH2 exerts its oncogenic function is through polycomb repressive complex 2 (PRC2)-mediated gene repression, which requires its histone methyltransferase activity. However, small-molecule inhibitors of EZH2 that selectively target 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 coactivators and thus raised the possibility of noncanonical 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 noncanonical function of EZH2 as a transcriptional activator upregulates 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 an 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 noncanonical EZH2 activity.
Cancer Science Institute of Singapore, and.
Junli
J
Yan
Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
Boheng
B
Li
Department of Haematology-Oncology, National University Cancer Institute of Singapore, and.
Baohong
B
Lin
Cancer Science Institute of Singapore, and.
Pei Tsung
PT
Lee
Cancer Science Institute of Singapore, and.
Tae-Hoon
TH
Chung
Cancer Science Institute of Singapore, and.
Joy
J
Tan
Cancer Science Institute of Singapore, and.
Chonglei
C
Bi
Cancer Science Institute of Singapore, and.
Xue Ting
XT
Lee
Department of Pathology, National University Health System, Singapore;
Viknesvaran
V
Selvarajan
Cancer Science Institute of Singapore, and Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pathology, National University Health System, Singapore;
Siok-Bian
SB
Ng
Cancer Science Institute of Singapore, and.
Henry
H
Yang
Department of Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Biopolis, Singapore.
Qiang
Q
Yu
Cancer Science Institute of Singapore, and Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute of Singapore, and.
Wee-Joo
WJ
Chng
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008954:Models, Biological; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors
C491488:EED protein, human; D006657:Histones; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; C430461:SUZ12 protein, human; D014157:Transcription Factors; D019000:Phosphotyrosine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D012319:RNA Polymerase II; D008239:Lysine