Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression

Abstract

Growth factor withdrawal inhibits cell cycle progression by stimulating expression of growth-arresting genes through the activation of Forkhead box O transcription factors such as FOXO3a, which binds to the FHRE-responsive elements of a number of target genes such as PUMA and GADD45a. Following exposure of cells to growth factors FOXO3a-mediated transcription is rapidly repressed. We determined that repression correlates with activation of PI3K/AKT pathway leading to FOXO3a phosphorylation and release of FOXO3a protein from PUMA and GADD45a chromatin. We show here that Myc significantly and selectively contributes to repression of FOXO-mediated expression of PUMA and GADD45a. We found that in Myc deprived cells inhibition of PUMA and GADD45a following serum stimulation is impaired and that Myc does not interfere with p53 induction of PUMA transcription. We observed that following activation, Myc is rapidly recruited to PUMA and GADD45a chromatin, with a concomitant switch in promoter occupancy from FOXO3a to Myc. Myc recruitment stimulates deacetylation of Histone H3 and H4 and methylation of lysine 9 in H3 (H3K9me2) on both PUMA and GADD45 chromatin. These data highlight a Myc role on cell growth by selectively inhibiting FOXO3a induced transcription of PUMA and GADD45.