Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer
Ahmed H. Ghobashi,
Truc T. Vuong,
Jane W. Kimani,
Christopher A. Ladaika,
Peter C. Hollenhorst,
Heather M. O’Hagan
Affiliations
Ahmed H. Ghobashi
Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University Bloomington, Bloomington, IN 47405, USA; Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Truc T. Vuong
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Jane W. Kimani
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Christopher A. Ladaika
Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University Bloomington, Bloomington, IN 47405, USA; Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Peter C. Hollenhorst
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Tumor Microenvironment & Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Heather M. O’Hagan
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Tumor Microenvironment & Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Corresponding author
Summary: 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.
