Oncogenic action of the exosome cofactor RBM7 by stabilization of CDK1 mRNA in breast cancer.
Oncogenic action of the exosome cofactor RBM7 by stabilization of CDK1 mRNA in breast cancer.
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DOI：
10.1038/s41523-020-00200-w
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发表时间：
2020
影响因子：
5.9
通讯作者：
Ding Q
中科院分区：
文献类型：
--
作者：
Xi PW;Zhang X;Zhu L;Dai XY;Cheng L;Hu Y;Shi L;Wei JF;Ding Q
RNA外泌体可以靶向特定的RNA，以通过不同的外泌体辅因子进行加工/降解。RNA结合基序蛋白7（RBM 7）是外泌体辅因子的重要组成部分，通过其RNA识别基序与mRNA中富含尿苷的序列特异性结合。然而，RBM 7在人类乳腺癌中的具体功能仍不清楚。在体外，实验表明，敲低RBM 7显着抑制乳腺癌细胞的增殖，同时诱导G1期细胞周期停滞;相反，当RBM 7过表达。同时，体内实验证实了RBM 7在乳腺癌中的致癌功能。RNA测序和后续通路分析发现，细胞周期蛋白依赖性激酶1（CDK 1）是RBM 7调控的主要基因之一。RBM 7的过表达增加了CDK 1的表达，而RBM 7的敲低降低了CDK 1的表达。RIP试验还发现RBM 7直接与CDK 1 mRNA结合。RBM 7可直接与CDK 1 mRNA 3′-UTR的富含AU的元件（战神）结合，延长CDK 1 mRNA的半衰期，从而提高其稳定性。更重要的是，通过敲低RBM 7降低的致癌活性可以通过在体外和体内过表达CDK 1来挽救，但突变的CDK 1失败了。以上结果提示，RBM 7可能通过与其3′-UTR区域的战神结合，稳定CDK 1 mRNA的表达，从而促进乳腺癌细胞增殖。正如我们所知，这是首次尝试将RNA外泌体与肿瘤发展联系起来，为RNA外泌体相关疾病的机制提供了新的见解。
RNA exosome can target the specific RNAs for their processing/degradation by distinct exosome cofactors. As a key component in exosome cofactors, RNA binding motif protein 7 (RBM7) shows the binding specificity for uridine-rich sequences in mRNAs via its RNA recognition motifs. However, the specific function of RBM7 in human breast cancer remains unclear. In vitro, experiments revealed that knockdown of RBM7 dramatically inhibited breast cancer cell proliferation, while inducing G1 cell cycle arrest; the opposite was true when RBM7 was overexpressed. Meanwhile, experiments in vivo confirmed the oncogenic function of RBM7 in breast cancer. RNA sequencing and the following pathway analysis found that cyclin-dependent kinase1 (CDK1) was one of the main gene regulated by RBM7. Overexpression of RBM7 increased CDK1 expression, while RBM7 knockdown decreased it. RIP assays additionally found that RBM7 bound directly to CDK1 mRNA. It was also showed that RBM7 could directly bind to the AU-rich elements (AREs) in 3′-UTR of CDK1 mRNA, which contributed to the stability of CDK1 mRNA by lengthening its half-life. More importantly, the oncogenic activity reduced by knockdown of RBM7 could be rescued by overexpression of CDK1 both in vitro and in vivo, but mutant CDK1 failed. All the evidences implied RBM7 promoted breast cancer cell proliferation by stabilizing CDK1 mRNA via binding to AREs in its 3′-UTR. As we knew, it was the first attempt to connect the RNA exosome to the tumor development, providing new insights into the mechanisms of RNA exosome-linked diseases.