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

// Francesca Petraglia 1, * , Abhishek A. Singh 2, * , Vincenzo Carafa 1, * , Angela Nebbioso 1 , Mariarosaria Conte 3 , Lucia Scisciola 1 , Sergio Valente 4 , Alfonso Baldi 5 , Amit Mandoli 2 , Valeria Belsito Petrizzi 6 , Concetta Ingenito 6 , Sandro De Falco 7 , Valeria Cicatiello 7 , Ivana Apicella 7 , Eva M. Janssen-Megens 2 , Bowon Kim 2 , Guoqiang Yi 2 , Colin Logie 2 , Simon Heath 8 , Menotti Ruvo 9 , Albertus T.J. Wierenga 10 , Paul Flicek 11 , Marie Laure Yaspo 12 , Veronique Della Valle 13 , Olivier Bernard 13 , Stefano Tomassi 14 , Ettore Novellino 14 , Alessandra Feoli 15 , Gianluca Sbardella 15 , Ivo Gut 8 , Edo Vellenga 10 , Hendrik G. Stunnenberg 2 , Antonello Mai 4, 16 , Joost H.A. Martens 2, 1 and Lucia Altucci 1 1 Dipartimento di Medicina di Precisione, Universita degli Studi della Campania Luigi Vanvitelli, Napoli 80138, Italy 2 Department of Molecular Biology, Radboud University, HB Nijmegen 6500, The Netherlands 3 IRCCS SDN, Napoli 80143, Italy 4 Dipartimento di Chimica e Tecnologie del Farmaco ‘Sapienza’ Universita, Roma 00185, Italy 5 Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita della Campania ‘Luigi Vanvitelli’, Caserta 81100, Italy 6 Ospedale Umberto I, Nocera Inferiore 84014, Italy 7 Istituto di Genetica e Biofisica, Napoli 80131, Italy 8 Centro Nacional de Analisis Genomico, Barcelona, Spain 9 Istituto di Biostrutture e Bioimmagini, Napoli, Italy 10 Department of Hematology, University of Groningen and University Medical Center Groningen, RB Groningen 9700, The Netherlands 11 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom 12 Max Planck Institute for Molecular Genetics, Berlin, Germany 13 Institute Gustave Roussy, Equipe labellisee Ligue Nationale contre le Cancer (LNCC), Universtite Paris-Saclay, INSERM U1170, Paris, France 14 Dipartimento di Farmacia, Universita di Napoli ‘Federico II’, Napoli 80131, Italy 15 Dipartimento di Farmacia, Universita degli Studi di Salerno, Fisciano I-84084, Italy 16 Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Roma 00185, Italy * These authors contributed equally to this work Correspondence to: Joost H.A. Martens, email: j.martens@ncmls.ru.nl Lucia Altucci, email: lucia.altucci@unicampania.it Keywords: cancer; epigenetics; apoptosis; acetylation; methylation Received: March 15, 2018      Accepted: May 02, 2018      Published: May 22, 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.