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

Autor: Valeria Cicatiello, Alfonso Baldi, Eva M. Janssen-Megens, Simon Heath, Olivier A. Bernard, Mariarosaria Conte, Edo Vellenga, Gianluca Sbardella, Alessandra Feoli, Antonello Mai, Francesca Petraglia, Concetta Ingenito, Bowon Kim, Valeria Belsito Petrizzi, Guoqiang Yi, Stefano Tomassi, Abhishek Singh, Angela Nebbioso, Ivo Gut, Paul Flicek, Albertus T. J. Wierenga, Marie-Laure Yaspo, Joost H.A. Martens, Hendrik G. Stunnenberg, Ivana Apicella, Lucia Scisciola, Sergio Valente, Ettore Novellino, Véronique Della Valle, Menotti Ruvo, Sandro De Falco, Amit Mandoli, Colin Logie, Vincenzo Carafa, Lucia Altucci
Přispěvatelé: Università degli studi della Campania 'Luigi Vanvitelli', Radboud university [Nijmegen], Institut de Recherche Vétérinaire de Tunisie (IRVT), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Ospedale Umberto I, Istituto di Biofisica e Genetica 'Adriano Buzzati Traverso', Consiglio Nazionale delle Ricerche (CNR), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), CNR – Istituto di Biostrutture e Bioimmagini, University Medical Center Groningen [Groningen] (UMCG), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli studi di Napoli Federico II, Università degli Studi di Salerno (UNISA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, This work was supported by BLUEPRINT (282510), Programma VALERE: Vanvitelli per la Ricerca, the Italian-Flag Project-EPIGEN, PRIN-20152TE5PK, the Italian association against cancer (AIRC-17217), the Dutch Cancer Foundation (KWF kun 2011–4937) and Netherlands organization for Scientific Research (NWO-VIDI)., 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, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL)
Rok vydání: 2018
Předmět:
Zdroj: Oncotarget, 9, 39, pp. 25630-25646
Oncotarget
Oncotarget, Impact journals, 2018, 9 (39), pp.25630-25646. ⟨10.18632/oncotarget.25428⟩
Oncotarget 9 (2018): 25630–25646. doi:10.18632/oncotarget.25428
info:cnr-pdr/source/autori:Petraglia F.; Singh A.A.; Carafa V.; Nebbioso A.; Conte M.; Scisciola L.; Valente S.; Baldi A.; Mandoli A.; Petrizzi V.B.; Ingenito C.; De Falco S.; Cicatiello V.; Apicella I.; Janssen-Megens E.M.; Kim B.; Yi G.; Logie C.; Heath S.; Ruvo M.; Wierenga A.T.J.; Flicek P.; Yaspo M.L.; Della Valle V.; Bernard O.; Tomassi S.; Novellino E.; Feoli A.; Sbardella G.; Gut I.; Vellenga E.; Stunnenberg H.G.; Mai A.; Martens J.H.A.; Altucci L./titolo:Combined HAT%2FEZH2 modulation leads to cancer-selective cell death/doi:10.18632%2Foncotarget.25428/rivista:Oncotarget/anno:2018/pagina_da:25630/pagina_a:25646/intervallo_pagine:25630–25646/volume:9
Oncotarget, 9(39), 25630-25646. Impact Journals LLC
Oncotarget, 9, 25630-25646
ISSN: 1949-2553
DOI: 10.18632/oncotarget.25428⟩
Popis: Contains fulltext : 197351.pdf (Publisher’s version ) (Open Access) 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.
Databáze: OpenAIRE
Externí odkaz: