Nature Communications · 2022 · 145 citations · 37 references
MedicineCancer BiologyOncologyCancer GeneticsMolecular OncologyOncogenesCancer EpigeneticsChromatinEpigenetic Regulation In CancerMyc Family OncogenesOncogenic Signaling PathwaysTumor Suppressor GenesEnzymatic InhibitionEzh2 FunctionMyc In NeuroblastomaMyc InhibitorsMyc Proteasomal DegradationN-myc RegulationProteasomal TurnoverTherapeutic Targeting Of Myc
Abstract Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCF FBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
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EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
Michael T. McCabe, Heidi M. Ott, Gopinath Ganji et al. · Nature · 2012 · 1.8K citations