Akt Inhibition Synergizes with Polycomb Repressive Complex 2 Inhibition in the Treatment of Multiple Myeloma

Overview

Journal Cancer Sci

Specialty Oncology

Date 2019 Oct 2

PMID 31571328

Citations 12

Authors

Mohamed Rizk

Ola Rizq

Motohiko Oshima

Yaeko Nakajima-Takagi

Shuhei Koide

Atsunori Saraya

Yusuke Isshiki

Tetsuhiro Chiba

Satoshi Yamazaki

Anqi Ma

Jian Jin

Atsushi Iwama

Naoya Mimura

Affiliations

Soon will be listed here.

Abstract

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. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some 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, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated 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 myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal 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 multiple myeloma.

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