Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells
Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells
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DOI：
10.1158/1535-7163.mct-15-0724
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发表时间：
2016-06-01
影响因子：
5.7
通讯作者：
Mariadason, John M.
中科院分区：
文献类型：
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作者：
Togel, Lars;Nightingale, Rebecca;Mariadason, John M.
溴结构域和末端外结构域 (BET) 蛋白家族的抑制剂可减弱多种肿瘤细胞系的增殖。这些效应至少部分是通过抑制 c-MYC 介导的。在结直肠癌中，由于 WNT/β-连环蛋白/TCF 信号传导过度活跃而引起的 c-MYC 过度表达是肿瘤进展的关键驱动因素；然而，针对这种癌基因的有效策略仍然难以捉摸。在这里，我们研究了 BET 抑制剂 (BETi) 对结直肠癌细胞增殖和 c-MYC 表达的影响。用 BETi JQ1 处理 20 种结直肠癌细胞系，鉴定出高度敏感细胞系的子集。 JQ1 敏感性在具有微卫星不稳定性的细胞系中较高，但与 CpG 岛甲基化表型、c-MYC 表达或扩增状态、BET 蛋白表达或 TP53、KRAS/BRAF 或 PIK3CA/PTEN 的突变状态无关。相反，JQ1 敏感性与 c-MYC mRNA 和蛋白质抑制的程度显着相关。 JQ1 介导的 c-MYC 抑制并非由于 β-连环蛋白/TCF 介导的转录普遍减弱，因为 JQ1 对其他 β-连环蛋白/TCF 靶基因或 β-连环蛋白/TCF 报告基因活性影响极小。 BETi 优先靶向超级增强子调节的基因，最近在 HCT116 细胞中发现了 c-MYC 中的超级增强子，该细胞招募了 BRD4 以及 WNT/β-catenin/TCF 和 MEK/ERK 途径的效应转录因子。将 c-MYC 与 JQ1 和这些途径的抑制剂联合靶向可进一步抑制 c-MYC 和 HCT116 细胞的增殖。这些发现表明，BETi 下调 c-MYC 表达并抑制结直肠癌细胞增殖，并确定了通过组合靶向 c-MYC 超级增强子来增强 BETi 对 c-MYC 抑制作用的策略。 (C)2016 AACR。
Inhibitors of the bromodomain and extraterminal domain (BET) protein family attenuate the proliferation of several tumor cell lines. These effects are mediated, at least in part, through repression of c-MYC. In colorectal cancer, overexpression of c-MYC due to hyperactive WNT/beta-catenin/TCF signaling is a key driver of tumor progression; however, effective strategies to target this oncogene remain elusive. Here, we investigated the effect of BET inhibitors (BETi) on colorectal cancer cell proliferation and c-MYC expression. Treatment of 20 colorectal cancer cell lines with the BETi JQ1 identified a subset of highly sensitive lines. JQ1 sensitivity was higher in cell lines with microsatellite instability but was not associated with the CpG island methylator phenotype, c-MYC expression or amplification status, BET protein expression, or mutation status of TP53, KRAS/BRAF, or PIK3CA/PTEN. Conversely, JQ1 sensitivity correlated significantly with the magnitude of c-MYC mRNA and protein repression. JQ1-mediated c-MYC repression was not due to generalized attenuation of beta-catenin/TCF-mediated transcription, as JQ1 had minimal effects on other beta-catenin/TCF target genes or beta-catenin/TCF reporter activity. BETi preferentially target super-enhancer-regulated genes, and a super-enhancer in c-MYC was recently identified in HCT116 cells to which BRD4 and effector transcription factors of the WNT/beta-catenin/TCF and MEK/ERK pathways are recruited. Combined targeting of c-MYC with JQ1 and inhibitors of these pathways additively repressed c-MYC and proliferation of HCT116 cells. These findings demonstrate that BETi downregulate c-MYC expression and inhibit colorectal cancer cell proliferation and identify strategies for enhancing the effects of BETi on c-MYC repression by combinatorial targeting the c-MYC super-enhancer. (C)2016 AACR.