Akt Inhibition Synergizes with PRC2 inhibition in the Treatment of Multiple Myeloma

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma (MM). However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, down-regulated EZH2 expression at the mRNA and protein levels via an interference with the Rb-E2F pathway, while EZH1 was compensatively up-regulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked the apoptosis of myeloma cells. RNA-seq analysis revealed the activation of FOXO signaling pathway after TAS-117 treatment. Ezh1 is one of the direct targets of Foxo transcription factors. FOXO3/4 mRNA and their downstream targets were up-regulated with the enhanced nuclear localization of the FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to the EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown down-regulated EZH1 expression. Collectively, the present results unravel (or investigate) some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for MM.