Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition.
Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition.
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DOI：
10.1158/1078-0432.ccr-16-2735
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Iwama A
中科院分区：
文献类型：
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作者：
Rizq O;Mimura N;Oshima M;Saraya A;Koide S;Kato Y;Aoyama K;Nakajima-Takagi Y;Wang C;Chiba T;Ma A;Jin J;Iseki T;Nakaseko C;Iwama A
EZH 2和EZH 1是多梳抑制复合物2（PRC 2）的催化组分，触发H3 K27（H3 K27 me 3）的三甲基化以抑制靶基因的转录，并参与多种癌症（包括多发性骨髓瘤和前列腺癌）的发病机制。在这里，我们研究了UNC 1999（EZH 2和EZH 1的双重抑制剂）与蛋白酶体抑制剂联合治疗多发性骨髓瘤和前列腺癌的临床前作用。在多发性骨髓瘤细胞系、原代患者细胞和异种移植模型中评价了UNC 1999和与蛋白酶体抑制剂联合给药的体外和体内疗效。进行RNA-seq和ChIP-seq以揭示多发性骨髓瘤中UNC 1999的靶点。在前列腺癌细胞系中验证了组合疗法的功效。蛋白酶体抑制剂通过废除RB-E2 F途径抑制EZH 2转录，从而使EZH 2依赖性多发性骨髓瘤细胞对UNC 1999的EZH 1抑制敏感。相应地，蛋白酶体抑制剂与UNC 1999的组合，而不是与EZH 2特异性抑制剂的组合，在体外诱导协同抗骨髓瘤活性。硼替佐米联合UNC 1999对骨髓瘤细胞的生长有明显的抑制作用。综合分析揭示了UNC 1999的几个直接靶点，包括肿瘤抑制基因NR 4A 1。UNC 1999对NR 4A 1的去阻遏导致对MYC的抑制，这通过与硼替佐米的组合而增强，表明PRC 2功能的协同阻断。值得注意的是，这种组合在前列腺癌细胞中也表现出很强的协同作用。我们的研究结果确定了EZH 2和EZH 1的双重抑制以及蛋白酶体抑制作为PRC 2依赖性癌症的有希望的基于表观遗传学的疗法。
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. In vitro and in vivo 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 EZH2 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 in vitro. Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo. Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1. Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, 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.