染色质修饰基因的突变在许多种癌症中经常发生。大多数机制研究关注它们的经典功能，而治疗方法则针对它们的酶活性。然而，最近的研究表明，染色质修饰因子的非经典功能在不同类型的癌症中可能同样重要且具有治疗作用。在癌症中展示这种双重作用的一个表观遗传调控因子是组蛋白甲基转移酶EZH2。EZH2是polycomb抑制复合物2（PRC2）的核心组分，对于细胞身份、分化、增殖、干细胞特性和可塑性起着至关重要的作用。尽管EZH2的调控功能和致癌活性大部分归因于其在组蛋白3上甲基化赖氨酸27（H3K27me3）的经典酶活性，即一种抑制性染色质标记，但最近的研究表明，与H3K27me3无关的非经典功能也对EZH2的致癌活性有贡献。与PRC2经典的由H3K27me3介导的抑制性活性相反，在复合物之外，EZH2可以直接与转录因子和癌基因相互作用，激活基因表达。对EZH2和其他表观遗传/染色质调控因子的这些非经典作用进行更深入的研究可能会揭示新的更有效的治疗策略。在这里，我们总结了EZH2非经典功能的主要发现以及它们与不同癌变方面的关系。Copyright © 2023 Zimmerman, Lin and Souroullas.

Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2's canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.Copyright © 2023 Zimmerman, Lin and Souroullas.