FOXO1 degradation by G9a-mediated methylation promotes cell proliferation in colon cancer

Post-translational modifications of Forkhead family transcription factor (FOXO1) have been known as important regulatory modes for its diverse activities. Several modifications of FOXO1 including acetylation, phosphorylation and ubiquitination were reported. However, lysine methylation of FOXO1 has not been identified yet. Here, we report that FOXO1 is methylated by G9a at K273 residue in vitro and in vivo. Methylation of FOXO1 by G9a increased interaction between FOXO1 and a specific E3 ligase skp2 and decreases FOXO1 protein stability. In addition, G9a expression was increased by insulin and resulted in insulin-mediated FOXO1 degradation by K273 methylation. Tissue array analysis indicates that G9a was overexpressed and FOXO1 was decreased in human colon cancer. Cell proliferation assays revealed that cell proliferation is increased by G9amediated FOXO1 methylation. In addition, fluorescence-activated cell sorting (FACS) analysis indicated that apoptosis is more increased in presence of FOXO1 compare with FOXO1 knock out cells. Therefore, G9a specific inhibitor, BIX-012494 can regulate cell proliferation and apoptosis via inhibition of FOXO1 methylation.

Biography :

Sang-Beom Seo has completed his PhD from The State University of New York at Binghamton, USA. He is currently working as a Professor in Chung-Ang University, Seoul, South Korea.

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