Rizq Ola, Mimura Naoya, Oshima Motohiko, Saraya Atsunori, Koide Shuhei, Kato Yuko, Aoyama Kazumasa, Nakajima-Takagi Yaeko, Wang Changshan, Chiba Tetsuhiro, Ma Anqi, Jin Jian, Iseki Tohru, Nakaseko Chiaki, Iwama Atsushi
Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan.
Clin Cancer Res. 2017 Aug 15;23(16):4817-4830. doi: 10.1158/1078-0432.CCR-16-2735. Epub 2017 May 10.
EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer. and efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in multiple myeloma. The efficacy of the combination therapy was validated in prostate cancer cell lines. Proteasome inhibitors repressed transcription via abrogation of the RB-E2F pathway, thereby sensitizing EZH2-dependent multiple myeloma cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic antimyeloma activity Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene Derepression of by UNC1999 resulted in suppression of , which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells. Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers. .
EZH2和EZH1是多梳抑制复合物2（PRC2）的催化成分，可引发组蛋白H3第27位赖氨酸的三甲基化（H3K27me3），从而抑制靶基因的转录，并与包括多发性骨髓瘤和前列腺癌在内的多种癌症的发病机制有关。在此，我们研究了EZH2和EZH1的双重抑制剂UNC1999与蛋白酶体抑制剂联合使用对多发性骨髓瘤和前列腺癌的临床前效应。在多发性骨髓瘤细胞系、原发性患者细胞以及异种移植模型中评估了UNC1999及其与蛋白酶体抑制剂联合使用的疗效。进行了RNA测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq）以揭示UNC1999在多发性骨髓瘤中的靶点。联合疗法的疗效在前列腺癌细胞系中得到验证。蛋白酶体抑制剂通过废除RB-E2F途径来抑制转录，从而使EZH2依赖性多发性骨髓瘤细胞对UNC1999抑制EZH1敏感。相应地，蛋白酶体抑制剂与UNC1999联合使用，而非与EZH2特异性抑制剂联合使用，可诱导协同抗骨髓瘤活性。硼替佐米与UNC1999联合使用可显著抑制骨髓瘤细胞的生长。综合分析揭示了UNC1999的几个直接靶点，包括肿瘤抑制基因。UNC1999对其去抑制导致了对[此处原文缺失相关内容]的抑制，而与硼替佐米联合使用可增强这种抑制，这表明对PRC2功能的协同阻断。值得注意的是，这种联合在前列腺癌细胞中也表现出很强的协同作用。我们的研究结果表明，EZH2和EZH1的双重抑制以及蛋白酶体抑制是一种有前景的针对PRC2依赖性癌症的基于表观遗传学的疗法。
