The BET-Bromodomain Inhibitor JQ1 synergized ABT-263 against colorectal cancer cells through suppressing c-Myc-induced miR-1271-5p expression
The BET-Bromodomain Inhibitor JQ1 synergized ABT-263 against colorectal cancer cells through suppressing c-Myc-induced miR-1271-5p expression
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BET-Bromodomain 抑制剂 JQ1 通过抑制 c-Myc 诱导的 miR-1271-5p 表达协同 ABT-263 对抗结直肠癌细胞
DOI：
10.1016/j.biopha.2017.09.087
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发表时间：
2017-11-01
影响因子：
7.5
通讯作者：
Yan, Jun
中科院分区：
文献类型：
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作者：
Wu, Zhenqian;Hu, Zedong;Yan, Jun
结直肠癌(CRC)细胞在小分子抑制剂ABT-263存在的情况下，通过上调抗凋亡基因Bcl2家族成员的表达而发生凋亡。然而，由于ABT-263与Mcl-1的低亲和力，在大多数实体肿瘤中逐渐产生了对ABT-263的耐药性。在这里，我们发现BET-溴域抑制剂JQ1，当与ABT-263联合使用时，协同降低Mcl-1蛋白水平，诱导细胞凋亡，并降低CRC HCT-15，HT-29和SW620细胞的存活率。随后的机制研究表明，c-Myc/miR-1271-5p/Noxa/Mcl-1途径是这种联合治疗的协同作用的基础。我们发现，协同作用的关键介质miR-1271-5p被c-Myc转录激活，并与NOXA的3‘-UTR结合以抑制其蛋白生产。JQ1和ABT-263联合处理抑制了c-Myc蛋白水平和c-Myc驱动的miR-1271-5p的表达，进而提高了Noxa的蛋白水平，最终促进了Mcl-1的降解。我们的发现为解决JQ1治疗结直肠癌过程中的耐药性提供了一种替代策略，并发现了一种新的依赖miR-1271-5p的NOXA基因表达调控机制。
Colorectal cancer (CRC) cells undergo apoptosis in the presence of the small-molecule inhibitor ABT-263 by up-regulating antiapoptotic Bcl-2 family members. However, the resistance to ABT-263 gradually developed in most solid tumors due to its low affinity to Mcl-1. Here, we found the BET-Bromodomain inhibitor JQ1, when combined with ABT-263, synergistically reduced Mcl-1 protein level, induced apoptosis, and decreased cell viability in the CRC HCT-15, HT-29 and SW620 cells. The subsequent mechanism study revealed that a pathway of c-Myc/miR-1271-5p/Noxa/Mcl-1 underlies the synergistic effect of such combination treatment. We discovered that miR-1271-5p, the key mediator for the synergistic effect, is transcriptionally activated by c-Myc, and binds to the 3'-UTR of noxa to inhibit its protein production. The combination treatment of JQ1 and ABT-263 inhibited c-Myc protein level and also c-Myc-driven expression of miR-1271-5p, subsequently increased the protein level of Noxa, and finally promotes the degradation of Mcl-1. Our findings provide an alternative strategy to resolve the resistance during treatment of CRC by JQ1, and also discovered a novel miR-1271-5p-dependent regulatory mechanism for gene expression of noxa.