Combined HAT/EZH2 modulation leads to cancer-selective cell death.

ABSTRACT: Epigenetic alterations have been associated with both pathogenesis and progression of cancer. By screening of library compounds, we identified a novel hybrid epi-drug MC2884, a HAT/EZH2 inhibitor, able to induce bona fide cancer-selective cell death in both solid and hematological cancers in vitro, ex vivo and in vivo xenograft models. Anticancer action was due to an epigenome modulation by H3K27me3, H3K27ac, H3K9/14ac decrease, and to caspase-dependent apoptosis induction. MC2884 triggered mitochondrial pathway apoptosis by up-regulation of cleaved-BID, and strong down-regulation of BCL2. Even aggressive models of cancer, such as p53^-/- or TET2^-/- cells, responded to MC2884, suggesting MC2884 therapeutic potential also for the therapy of T

SUBMITTER: Petraglia F 

PROVIDER: S-EPMC5986654 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature