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

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

doi:10.18632/oncotarget.25428

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.

Highlights

Massive parallel sequencing of cancer genomes has identified a myriad of mutant epigenetic enzymes responsible for histone acetylation and methylation, and DNA methylation [1]
To identify novel epigenetic drugs with hybrid actions, we screened a panel of compounds of natural or synthetic origin harboring potential chromatin activity and identified MC2884 (Figure 1A) as a promising candidate
We investigated the effects of MC2884 on cell death induction in several cancer cell lines derived from leukemias (NB4, HL-60, U937) or solid tumors, such as colon (HCT116) and breast (MDA-MB231, MCF7) (Figure 1C)

Summary

Introduction

Massive parallel sequencing of cancer genomes has identified a myriad of mutant epigenetic enzymes responsible for histone acetylation and methylation, and DNA methylation [1]. Genome sequencing of de novo AML revealed the presence of at least one nonsynonymous mutation in 44% of DNA methylation-related genes and 30% of chromatin-modifying genes [1, 16]. This astonishing finding highlights the dual etiology - epigenetic and genetic - phenomena driving leukemogenesis [17, 18] and likely other cancers [19]. Inhibitors targeting the methyltransferases DOT1L, EZH2 or the demethylase LSD1 are in clinical trials [29] Whether more of these selective or more general chromatin regulators are needed is still under investigation [30].

Methods

Results

Conclusion