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

Francesca Petraglia, Abhishek A Singh, Vincenzo Carafa, Angela Nebbioso, Mariarosaria Conte, Lucia Scisciola, Sergio Valente, Alfonso Baldi, Amit Mandoli, Valeria Belsito Petrizzi, Concetta Ingenito, Sandro De Falco, Valeria Cicatiello, Ivana Apicella, Eva M Janssen-Megens, Bowon Kim, Guoqiang Yi, Colin Logie, Simon Heath, Menotti RuvoAlbertus T J Wierenga, Paul Flicek, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Stefano Tomassi, Ettore Novellino, Alessandra Feoli, Gianluca Sbardella, Ivo Gut, Edo Vellenga, Hendrik G Stunnenberg, Antonello Mai, Joost H A Martens, Lucia Altucci

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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 TP53 or TET2-deficient human cancers. MC2884 induced massive apoptosis in ex vivo human primary leukemia blasts with poor prognosis in vivo, by targeting BCL2 expression. MC2884-treatment reduced acetylation of the BCL2 promoter at higher level than combined p300 and EZH2 inhibition. This suggests a key role for BCL-2 reduction in potentiating responsiveness, also in combination therapy with BCL2 inhibitors. Finally, we identified both the mechanism of MC2884 action as well as a potential therapeutic scheme of its use. Altogether, this provides proof of concept for the use of epi-drugs coupled with epigenome analyses to 'personalize' precision medicine.

Original languageEnglish
Pages (from-to)25630-25646
Number of pages17
JournalOncotarget
Volume9
Issue number39
DOIs
Publication statusPublished - 2018

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