Oncogenic Y641 mutations in EZH2 prevent Jak2/β-TrCP-mediated degradation.
EZH2 (enhancer of zeste homolog 2) is a critical enzymatic subunit of the polycomb repressive complex 2 (PRC2), which trimethylates histone H3 (H3K27) to mediate gene repression. Somatic mutations, overexpression and hyperactivation of EZH2 have been implicated in the pathogenesis of several forms of cancer. In particular, recurrent gain-of-function mutations targeting EZH2 Y641 occur most frequently in follicular lymphoma and aggressive diffuse large B-cell lymphoma and are associated with H3K27me3 hyperactivation, which contributes to lymphoma pathogenesis. However, the post-translational mechanisms of EZH2 regulation are not completely understood. Here we show that EZH2 is a novel interactor and substrate of the SCF E3 ubiquitin ligase β-TrCP (FBXW1). β-TrCP ubiquitinates EZH2 and Jak2-mediated phosphorylation on Y641 directs β-TrCP-mediated EZH2 degradation. RNA interference-mediated silencing of β-TrCP or inhibition of Jak2 results in EZH2 stabilization with attendant increase in H3K27 trimethylation activity. Importantly, the EZH2(Y641) mutants recurrently implicated in lymphoma pathogenesis are unable to bind β-TrCP. Further, endogenous EZH2(Y641) mutants in lymphoma cells exhibit increased EZH2 stability and H3K27me3 hyperactivity. Our studies demonstrate that β-TrCP has an important role in controlling H3K27 trimethylation activity and lymphoma pathogenesis by targeting EZH2 for degradation.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Sahasrabuddhe
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Chen
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Chung
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Velusamy
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Lim
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Elenitoba-Johnson
D000071221:Enhancer of Zeste Homolog 2 Protein; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology*; D008223:Lymphoma / Q000209:etiology; D008745:Methylation; D009154:Mutation; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology*
D006657:Histones; D044844:beta-Transducin Repeat-Containing Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D046988:Proteasome Endopeptidase Complex