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
Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli 80138, Italy.
Department of Molecular Biology, Radboud University, HB Nijmegen 6500, The Netherlands.
Oncotarget. 2018 May 22;9(39):25630-25646. doi: 10.18632/oncotarget.25428.
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 cancer-selective cell death in both solid and hematological cancers , and 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 human primary leukemia blasts with poor prognosis , 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.
表观遗传改变与癌症的发病机制和进展均相关。通过对文库化合物的筛选，我们鉴定出一种新型的混合表位药物MC2884，一种组蛋白乙酰转移酶/增强子结合蛋白2（HAT/EZH2）抑制剂，它能够在实体癌和血液系统癌症以及异种移植模型中诱导癌症选择性细胞死亡。抗癌作用归因于由H3K27me3、H3K27ac、H3K9/14ac减少所介导的表观基因组调节以及半胱天冬酶依赖性凋亡诱导。MC2884通过上调裂解的BID以及强烈下调BCL2触发线粒体途径凋亡。即使是侵袭性癌症模型，如p53或TET2缺陷细胞，也对MC2884有反应，这表明MC2884在治疗TP53或TET2缺陷的人类癌症方面也具有治疗潜力。MC2884通过靶向BCL2表达在预后不良的人类原发性白血病母细胞中诱导大量凋亡。与联合抑制p300和EZH2相比，MC2884处理在更高水平上降低了BCL2启动子的乙酰化。这表明BCL-2的减少在增强反应性中起关键作用，在与BCL2抑制剂的联合治疗中也是如此。最后，我们确定了MC2884的作用机制及其潜在的治疗方案。总之，这为使用表位药物结合表观基因组分析来“个性化”精准医学提供了概念验证。
