RNA-binding motif protein 10 induces apoptosis and suppresses proliferation by activating p53

Abstract

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.