EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Liyuan Wang, Chan Chen, Zemin Song, Honghong Wang, Minghui Ye, Donghai Wang, Wenqian Kang, Hudan Liu and Guoliang Qing ()
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Liyuan Wang: Zhongnan Hospital of Wuhan University
Chan Chen: Wuhan University
Zemin Song: Wuhan University
Honghong Wang: Wuhan University
Minghui Ye: Wuhan University
Donghai Wang: Wuhan University
Wenqian Kang: Wuhan University
Hudan Liu: Wuhan University
Guoliang Qing: Zhongnan Hospital of Wuhan University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27609-6

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