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 SCFFBW7 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.
Highlights
Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer
Administration of GSK126 at the dose of 25 mg/kg already exhibited significant in vivo efficacy in terms of H3K27me[3] depletion (Fig. 5f, compare lane 5 vs lanes 1 and 2), yet the MYCN abundance and xenograft tumor growth was largely unchanged at this dose (Fig. 5e), suggesting that MYCN stabilization is more critical for EZH2 oncogenic function in the current tumor contexts. All of these findings provide strong evidence demonstrating that a non-catalytic role of EZH2 in MYCN stabilization and tumor progression in vivo, arguing that the enzymatic inhibitors in clinical development may be impotent in MYC(N)-driven neuroblastomas unless they are capable of depleting EZH2 and/or MYC(N)
We identified EZH2, independent of its methyltransferase activity, as an essential regulator of MYC(N) stabilization and the stabilized MYC(N) proteins in turn as essential EZH2 oncogenic effectors
Summary
Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. 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. Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity[8,12], it remains undefined whether modulation of H3K27 trimethylation is the prominent mechanism whereby EZH2 promotes cancer. We seek to investigate the regulatory mechanisms and involving biological relevance in the current study
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