Activation of AKT induces EZH2-mediated 0 -catenin trimethylation in colorectal cancer

Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/beta-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 beta-catenin at lysine 49, which increased beta-catenin's binding to the chromatin. Additionally, EZH2-mediated beta-catenin trimethylation induced b-catenin to interact with TCF1 and RNA polymerase II and resulted in dramatic gains in genomic regions with beta-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/beta-catenin axis in CRC.