结直肠癌（CRC）的发展部分通过不同信号通路的非调控来实现，包括激活WNT/β-连接蛋白和PI3K/AKT通路。此外，在CRC中EZH2赖氨酸甲基转移酶2常见异常表达。EZH2通过三甲基化组蛋白H3的赖氨酸27发挥经典的基因转录抑制作用，但其也具有非组蛋白底物。我们在这里证明，在CRC中，活性AKT通过丝氨酸21磷酸化EZH2。AKT对EZH2的磷酸化诱导EZH2与β-连接蛋白在赖氨酸49位点发生相互作用并发生甲基化，增加了β-连接蛋白与染色质的结合。此外，EZH2介导的β-连接蛋白三甲基化促使其与TCF1和RNA聚合酶II发生相互作用，并导致具有β-连接蛋白占用的基因组区域的显著增加。EZH2催化抑制减少了具有活性AKT的CRC细胞的干细胞特性，但增加了其迁移表型。总的来说，我们证明了EZH2通过AKT/EZH2/β-连接蛋白轴调节了CRC中AKT诱导的基因表达变化。 © 2023 作者

Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Additionally, the lysine methyltransferase enhancer of zeste homologue 2 (EZH2) is commonly overexpressed in CRC. EZH2 canonically represses gene transcription by trimethylating lysine 27 of histone H3, but also has non-histone substrates. Here, we demonstrated that in CRC, active AKT phosphorylated EZH2 on serine 21. Phosphorylation of EZH2 by AKT induced EZH2 to interact with and methylate β-catenin at lysine 49, which increased β-catenin's binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin to interact with TCF1 and RNA polymerase II and resulted in dramatic gains in genomic regions with β-catenin occupancy. EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC.© 2023 The Author(s).