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  • Title: Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells.
    Author: Arai T, Kano F, Murata M.
    Journal: Genes Cells; 2015 Apr; 20(4):340-57. PubMed ID: 25736587.
    Abstract:
    Forkhead box O1 (FOXO1) is an important target for insulin. It is widely accepted that insulin-induced phosphorylation of FOXO1 by Akt leads to its nuclear exclusion and results in the inhibition of FOXO1-mediated transcription of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1 (PCK1) in hepatocytes. However, many results that contradict this model have accumulated. Here, we provide a new mechanism for insulin-dependent repression of FOXO1-mediated transcription. We showed insulin-induced translocation of endogenous Ser256-phosphorylated FOXO1, which is essential for regulation of FOXO1-mediated transcription, from nuclear speckles to the nuclear periphery. This insulin-dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N-methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region. Notably, our results suggest that FOXO1 uses nucleoporin 98 kDa NUP98 for this transcriptional regulation. These results provide a new insight into various FOXO1-mediated transcriptional regulation and FOXO1-mediated essential biological pathways.
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