description |
Histone methyltransferases EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger H3K27me3 to repress the transcription of target genes and are implicated in tumorigenesis. Here, we demonstrate PRC2-dependency in multiple myeloma (MM) cells using EZH2 knockdown and PRC2 inhibition by UNC1999, a dual inhibitor of EZH2 and EZH1. Bortezomib, the first line therapeutic agent for MM, markedly downregulates EZH2 via abrogation of RB-E2F pathway, while maintaining H3K27me3 mark with residual EZH1. Importantly, bortezomib exerts synergistic effects with UNC1999, but not EZH2-specific inhibitors, suggesting that the dual inhibition of EZH2 and EZH1 sensitizes MM cells to proteasome inhibition. Genome wide analysis revealed that the combination therapy enhances de-repression of PRC2 target genes including NR4A1 and the subsequent MYC suppression. This combination also exhibits strong synergy in prostate cancer cells, indicating that the dual inhibition of PRC2 together with proteasome inhibition represents a novel therapeutic strategy for PRC2-dependent tumors. |