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

• Published in: Oncotarget Vol. 9; no. 39; pp. 25630 - 25646
• Main Authors: Petraglia, Francesca, Singh, Abhishek A., Carafa, Vincenzo, Nebbioso, Angela, Conte, Mariarosaria, Scisciola, Lucia, Valente, Sergio, Baldi, Alfonso, Mandoli, Amit, Petrizzi, Valeria Belsito, Ingenito, Concetta, De Falco, Sandro, Cicatiello, Valeria, Apicella, Ivana, Janssen-Megens, Eva M., Kim, Bowon, Yi, Guoqiang, Logie, Colin, Heath, Simon, Ruvo, Menotti, Wierenga, Albertus T.J., Flicek, Paul, Yaspo, Marie Laure, Della Valle, Veronique, Bernard, Olivier, Tomassi, Stefano, Novellino, Ettore, Feoli, Alessandra, Sbardella, Gianluca, Gut, Ivo, Vellenga, Edo, Stunnenberg, Hendrik G., Mai, Antonello, Martens, Joost H.A., Altucci, Lucia
• Format: Journal Article
• Language: English
• Published: United States Impact journals 22.05.2018; Impact Journals LLC
• Subjects: Cancer; Life Sciences; Research Paper; acetylation; apoptosis; cancer; methylation; epigenetics
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.25428

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 cancer-selective cell death in both solid and hematological cancers , and 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 human primary leukemia blasts with poor prognosis , 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.