Dicer regulates non-homologous end joining and is associated with chemosensitivity in colon cancer patients
Dicer regulates non-homologous end joining and is associated with chemosensitivity in colon cancer patients
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Dicer 调节非同源末端连接并与结肠癌患者的化疗敏感性相关
DOI：
10.1093/carcin/bgx059
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发表时间：
2017-09-01
期刊：
影响因子：
4.7
通讯作者：
Tang, Kai-Fu
中科院分区：
文献类型：
--
作者：
Chen, Xiao;Li, Wen-Feng;Tang, Kai-Fu
DNA双链断裂（DSB）修复是人类肿瘤化疗耐药的重要机制。Dicer通过促进同源重组参与DSB修复。然而，Dicer是否参与非同源末端连接（non-homologous end joining， NHEJ）尚不清楚。在这里，我们研究了Dicer是否调节结肠癌细胞的NHEJ和化疗敏感性。利用我们最近开发的NHEJ实验，我们发现通过I-SceI切割引入DSB导致Dicer上调。Dicer敲低增加了SIRT7的结合，降低了DSB位点的H3K18Ac（组蛋白H3的乙酰化赖氨酸18）水平，从而抑制了NHEJ因子向DSB位点的募集，抑制了NHEJ。Dicer过表达降低了SIRT7的结合，增加了DSB位点的H3K18Ac水平，促进了NHEJ因子向DSB的募集，适度增强了NHEJ。Dicer敲低和过表达分别增加和降低结肠癌细胞的化学敏感性。结肠癌患者组织中Dicer蛋白表达与化疗耐药直接相关。我们的研究结果揭示了Dicer在nhej介导的DSB修复中的功能，以及Dicer表达与结肠癌患者化疗耐药的关系。
DNA double-strand break (DSB) repair is an important mechanism underlying chemotherapy resistance in human cancers. Dicer participates in DSB repair by facilitating homologous recombination. However, whether Dicer is involved in non-homologous end joining (NHEJ) remains unknown. Here, we addressed whether Dicer regulates NHEJ and chemosensitivity in colon cancer cells. Using our recently developed NHEJ assay, we found that DSB introduction by I-SceI cleavage leads to Dicer upregulation. Dicer knockdown increased SIRT7 binding and decreased the level of H3K18Ac (acetylated lysine 18 of histone H3) at DSB sites, thereby repressing the recruitment of NHEJ factors to DSB sites and inhibiting NHEJ. Dicer overexpression reduced SIRT7 binding and increased the level of H3K18Ac at DSB sites, promoting the recruitment of NHEJ factors to DSBs and moderately enhancing NHEJ. Dicer knockdown and overexpression increased and decreased, respectively, the chemosensitivity of colon cancer cells. Dicer protein expression in colon cancer tissues of patients was directly correlated with chemoresistance. Our findings revealed a function of Dicer in NHEJ-mediated DSB repair and the association of Dicer expression with chemoresistance in colon cancer patients.