Ghobashi, Ahmed H.Vuong, Truc T.Kimani, Jane W.Ladaika, Christopher A.Hollenhorst, Peter C.O’Hagan, Heather M.2024-03-112024-03-112023-08-16Ghobashi AH, Vuong TT, Kimani JW, Ladaika CA, Hollenhorst PC, O'Hagan HM. Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. iScience. 2023;26(9):107630. Published 2023 Aug 16. doi:10.1016/j.isci.2023.107630https://hdl.handle.net/1805/39149Colorectal 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalCancerEpigeneticsMolecular biologyArticle