Combined HAT/EZH2 modulation leads to cancer-selective cell death
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Francesca Petraglia1,*, Abhishek A. Singh2,*, Vincenzo Carafa1,*, Angela Nebbioso1, Mariarosaria Conte3, Lucia Scisciola1, Sergio Valente4, Alfonso Baldi5, Amit Mandoli2, Valeria Belsito Petrizzi6, Concetta Ingenito6, Sandro De Falco7, Valeria Cicatiello7, Ivana Apicella7, Eva M. Janssen-Megens2, Bowon Kim2, Guoqiang Yi2, Colin Logie2, Simon Heath8, Menotti Ruvo9, Albertus T.J. Wierenga10, Paul Flicek11, Marie Laure Yaspo12, Veronique Della Valle13, Olivier Bernard13, Stefano Tomassi14, Ettore Novellino14, Alessandra Feoli15, Gianluca Sbardella15, Ivo Gut8, Edo Vellenga10, Hendrik G. Stunnenberg2, Antonello Mai4,16, Joost H.A. Martens2,1 and Lucia Altucci1
1Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli 80138, Italy
2Department of Molecular Biology, Radboud University, HB Nijmegen 6500, The Netherlands
3IRCCS SDN, Napoli 80143, Italy
4Dipartimento di Chimica e Tecnologie del Farmaco ‘Sapienza’ Università, Roma 00185, Italy
5Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università della Campania ‘Luigi Vanvitelli’, Caserta 81100, Italy
6Ospedale Umberto I, Nocera Inferiore 84014, Italy
7Istituto di Genetica e Biofisica, Napoli 80131, Italy
8Centro Nacional de Análisis Genómico, Barcelona, Spain
9Istituto di Biostrutture e Bioimmagini, Napoli, Italy
10Department of Hematology, University of Groningen and University Medical Center Groningen, RB Groningen 9700, The Netherlands
11European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
12Max Planck Institute for Molecular Genetics, Berlin, Germany
13Institute Gustave Roussy, Equipe labellisée Ligue Nationale contre le Cancer (LNCC), Universtité Paris-Saclay, INSERM U1170, Paris, France
14Dipartimento di Farmacia, Università di Napoli ‘Federico II’, Napoli 80131, Italy
15Dipartimento di Farmacia, Università degli Studi di Salerno, Fisciano I-84084, Italy
16Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Roma 00185, Italy
*These authors contributed equally to this work
Joost H.A. Martens, email: [email protected]
Lucia Altucci, email: [email protected]
Keywords: cancer; epigenetics; apoptosis; acetylation; methylation
Received: March 15, 2018 Accepted: May 02, 2018 Published: May 22, 2018
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.
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