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

Francesca Petraglia, Abhishek A. Singh, Vincenzo Carafa, Angela Nebbioso, Mariarosaria Conte, Lucia Scisciola, Sergio Valente, Alfonso Baldi, Amit Mandoli, Valeria Belsito Petrizzi, Concetta Ingenito, Sandro De Falco, Valeria Cicatiello, Ivana Apicella, Eva M. Janssen-Megens, Bowon Kim, Guoqiang Yi, Colin Logie, Simon Heath, Menotti RuvoAlbertus T.J. Wierenga, Paul Flicek, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Stefano Tomassi, Ettore Novellino, Alessandra Feoli, Gianluca Sbardella, Ivo Gut, Edo Vellenga, Hendrik G. Stunnenberg, Antonello Mai, Joost H.A. Martens, Lucia Altucci

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)25630-25646
Number of pages17
JournalOncotarget
Volume9
Issue number39
DOIs
Publication statusPublished - May 22 2018

Fingerprint

Cell Death
Precision Medicine
Neoplasms
Apoptosis
Therapeutics
Acetylation
Caspases
Heterografts
Epigenomics
Pharmaceutical Preparations
Libraries
Leukemia
Up-Regulation
Down-Regulation

Keywords

  • Acetylation
  • Apoptosis
  • Cancer
  • Epigenetics
  • Methylation

ASJC Scopus subject areas

  • Oncology

Cite this

Petraglia, F., Singh, A. A., Carafa, V., Nebbioso, A., Conte, M., Scisciola, L., ... Altucci, L. (2018). Combined HAT/EZH2 modulation leads to cancer-selective cell death. Oncotarget, 9(39), 25630-25646. https://doi.org/10.18632/oncotarget.25428

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, Vol. 9, No. 39, 22.05.2018, p. 25630-25646.

Research output: Contribution to journalArticle

Petraglia, F, Singh, AA, Carafa, V, Nebbioso, A, Conte, M, Scisciola, L, Valente, S, Baldi, A, Mandoli, A, Petrizzi, VB, Ingenito, C, De Falco, S, Cicatiello, V, Apicella, I, Janssen-Megens, EM, Kim, B, Yi, G, Logie, C, Heath, S, Ruvo, M, Wierenga, ATJ, Flicek, P, Yaspo, ML, Della Valle, V, Bernard, O, Tomassi, S, Novellino, E, Feoli, A, Sbardella, G, Gut, I, Vellenga, E, Stunnenberg, HG, Mai, A, Martens, JHA & Altucci, L 2018, 'Combined HAT/EZH2 modulation leads to cancer-selective cell death', Oncotarget, vol. 9, no. 39, pp. 25630-25646. https://doi.org/10.18632/oncotarget.25428
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 May 22;9(39):25630-25646. https://doi.org/10.18632/oncotarget.25428
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. / Combined HAT/EZH2 modulation leads to cancer-selective cell death. In: Oncotarget. 2018 ; Vol. 9, No. 39. pp. 25630-25646.
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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.",
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AU - Conte, Mariarosaria

AU - Scisciola, Lucia

AU - Valente, Sergio

AU - Baldi, Alfonso

AU - Mandoli, Amit

AU - Petrizzi, Valeria Belsito

AU - Ingenito, Concetta

AU - De Falco, Sandro

AU - Cicatiello, Valeria

AU - Apicella, Ivana

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AU - Logie, Colin

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AU - Wierenga, Albertus T.J.

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AU - Della Valle, Veronique

AU - Bernard, Olivier

AU - Tomassi, Stefano

AU - Novellino, Ettore

AU - Feoli, Alessandra

AU - Sbardella, Gianluca

AU - Gut, Ivo

AU - Vellenga, Edo

AU - Stunnenberg, Hendrik G.

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AU - Martens, Joost H.A.

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N2 - 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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