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

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Listed:
  • Liyuan Wang

    (Zhongnan Hospital of Wuhan University
    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
    Wuhan University)

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.

Suggested Citation

  • Liyuan Wang & Chan Chen & Zemin Song & Honghong Wang & Minghui Ye & Donghai Wang & Wenqian Kang & Hudan Liu & Guoliang Qing, 2022. "EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27609-6
    DOI: 10.1038/s41467-021-27609-6
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    Cited by:

    1. Minhui Ye & Yingzhe Fang & Lu Chen & Zemin Song & Qing Bao & Fei Wang & Hao Huang & Jin Xu & Ziwen Wang & Ruijing Xiao & Meng Han & Song Gao & Hudan Liu & Baishan Jiang & Guoliang Qing, 2024. "Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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