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

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Petraglia, Francesca
• dc.contributor.author Heath, Simon
• dc.contributor.author Gut, Ivo Glynne
• dc.contributor.author Altucci, Lucia
• dc.date.accessioned 2019-11-28T08:29:09Z
• dc.date.available 2019-11-28T08:29:09Z
• dc.date.issued 2018
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L et al. Combined HAT/EZH2 modulation leads to cancer-selective cell death. Oncotarget. 2018; 9(39):25630-25646. DOI 10.18632/oncotarget.25428
• dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.25428
• dc.identifier.issn 1949-2553
• dc.identifier.uri http://hdl.handle.net/10230/43025
• dc.language.iso eng
• dc.publisher Impact Journals
• dc.relation.ispartof Oncotarget. 2018; 9(39):25630-25646
• dc.rights © Petraglia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0) (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/3.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Epigenetics
• dc.subject.keyword Apoptosis
• dc.subject.keyword Acetylation
• dc.subject.keyword Methylation
• dc.title Combined HAT/EZH2 modulation leads to cancer-selective cell death
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion