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.

Combined HAT/EZH2 modulation leads to cancer-selective cell death / 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. - In: ONCOTARGET. - ISSN 1949-2553. - 9:39(2018), pp. 25630-25646. [10.18632/oncotarget.25428]

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

Valente, Sergio;Tomassi, Stefano;Sbardella, Gianluca;Mai, Antonello;
2018

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.
2018
acetylation; apoptosis; cancer; epigenetics; methylation; oncology
01 Pubblicazione su rivista::01a Articolo in rivista
Combined HAT/EZH2 modulation leads to cancer-selective cell death / 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. - In: ONCOTARGET. - ISSN 1949-2553. - 9:39(2018), pp. 25630-25646. [10.18632/oncotarget.25428]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1147237
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