Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China.
Nat Commun. 2022 Jan 10;13(1):12. doi: 10.1038/s41467-021-27609-6.
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 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.
目前的研究表明，EZH2 可直接与 MYC 家族癌蛋白 MYC 和 MYCN 相互作用，并以不依赖于其甲基转移酶活性的方式促进它们的稳定。通过与 SCF 泛素连接酶竞争结合 MYC 和 MYCN，EZH2 可拮抗 FBW7 介导的 MYC(N)多泛素化和蛋白酶体降解。EZH2 的耗竭（而非酶抑制）可诱导强烈的 MYC(N)降解，并抑制 MYC(N)驱动的神经母细胞瘤和小细胞肺癌中的肿瘤细胞生长。在这里，我们将 MYC 家族蛋白鉴定为 EZH2 的致癌效应子，EZH2 的药理学降解剂则可作为潜在的 MYC(N) 靶向癌症治疗药物，这表明由 MYC(N)驱动的癌症可能对目前处于临床开发阶段的经典 EZH2 酶抑制剂产生固有耐药性。
