TY - JOUR
T1 - Combined HAT/EZH2 modulation leads to cancer-selective cell death
AU - Petraglia, Francesca
AU - Singh, Abhishek A.
AU - Carafa, Vincenzo
AU - Nebbioso, Angela
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
AU - Janssen-Megens, Eva M.
AU - Kim, Bowon
AU - Yi, Guoqiang
AU - Logie, Colin
AU - Heath, Simon
AU - Ruvo, Menotti
AU - Wierenga, Albertus T.J.
AU - Flicek, Paul
AU - Yaspo, Marie Laure
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.
AU - Mai, Antonello
AU - Martens, Joost H.A.
AU - Altucci, Lucia
N1 - Publisher Copyright:
© Petraglia et al.
PY - 2018/5/22
Y1 - 2018/5/22
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.
AB - 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.
KW - Acetylation
KW - Apoptosis
KW - Cancer
KW - Epigenetics
KW - Methylation
UR - http://www.scopus.com/inward/record.url?scp=85047400725&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25428
DO - 10.18632/oncotarget.25428
M3 - Article
AN - SCOPUS:85047400725
SN - 1949-2553
VL - 9
SP - 25630
EP - 25646
JO - Oncotarget
JF - Oncotarget
IS - 39
ER -