Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.
Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.
Oncogene. 2020 Jan;39(5):1031-1040. doi: 10.1038/s41388-019-1034-9. Epub 2019 Oct 7.
RNA-binding motif protein 10 (RBM10) is an RNA-binding protein frequently deleted or mutated in lung cancer cells. Recent reports showed that the knockdown of RBM10 in human cancer cells enhances the growth of mouse tumor xenografts, suggesting that RBM10 acts as a tumor suppressor. RBM10 also regulates alternative splicing and controls cancer cell proliferation. However, the underlying molecular mechanisms for its tumor suppression role remain largely unclear. Here, we for the first time report that RBM10 can induce apoptosis and inhibit cancer cell proliferation by activating p53. Our analysis of cancer genomic databases showed that patients with wild-type RBM10 and p53 survive longer than do those with mutated p53 or less RBM10. RBM10 overexpression markedly inhibited mitochondrial respiration, cell migration and proliferation of various cancer cells that harbor wild-type p53. Also, RBM10 overexpression elongated p53's half-life by disrupting MDM2-p53 interaction and subsequently repressing p53 ubiquitination, whereas knockdown of RBM10 decreased p53 stability. Altogether, our results demonstrate that RBM10 inhibits cancer cell proliferation and induces apoptosis in part by blocking the MDM2-p53 feedback loop.
RNA 结合基序蛋白 10（RBM10）是一种在肺癌细胞中经常缺失或突变的 RNA 结合蛋白。最近的报告表明，在人类癌细胞中敲低 RBM10 会增强小鼠肿瘤异种移植物的生长，这表明 RBM10 作为一种肿瘤抑制因子发挥作用。RBM10 还调节选择性剪接并控制癌细胞增殖。然而，其肿瘤抑制作用的潜在分子机制在很大程度上仍不清楚。在这里，我们首次报道 RBM10 可以通过激活 p53 诱导细胞凋亡并抑制癌细胞增殖。我们对癌症基因组数据库的分析表明，具有野生型 RBM10 和 p53 的患者比具有突变型 p53 或较少 RBM10 的患者存活时间更长。RBM10 的过表达显著抑制了具有野生型 p53 的各种癌细胞的线粒体呼吸、细胞迁移和增殖。此外，RBM10 过表达通过破坏 MDM2-p53 相互作用并随后抑制 p53 泛素化来延长 p53 的半衰期，而 RBM10 的敲低则降低了 p53 的稳定性。总之，我们的结果表明，RBM10 通过阻断 MDM2-p53 反馈环部分抑制癌细胞增殖并诱导细胞凋亡。
