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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.

SUBMITTER: Jung JH

PROVIDER: S-EPMC6994357 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Jung Ji Hoon JH Lee Hyemin H Cao Bo B Liao Peng P Zeng Shelya X SX Lu Hua H

Oncogene 20191007 5

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 ...[more]

PMID: 31591476

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Project description:BackgroundLong non-coding RNAs play an important role in tumorigenesis, hence, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. Recently, the downregulation of lncRNA MEG3 has been observed in various human cancers. However, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to examine the expression pattern of MEG3 in NSCLC and to evaluate its biological role and clinical significance in tumor progression.MethodsExpression of MEG3 was analyzed in 44 NSCLC tissues and 7 NSCLC cell lines by qRT-PCR. Over-expression approaches were used to investigate the biological functions of MEG3 in NSCLC cells. Bisulfite sequencing was used to investigate DNA methylation on MEG3 expression. The effect of MEG3 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by Hoechst staining and Flow-cytometric analysis. NSCLC cells transfected with pCDNA-MEG3 were injection into nude mice to study the effect of MEG3 on tumorigenesis in vivo . Protein levels of MEG3 targets were determined by western blot analysis. Differences between groups were tested for significance using Student's t-test (two-tailed).ResultsMEG3 expression was decreased in non-small cell lung cancer (NSCLC) tumor tissues compared with normal tissues, and associated with advanced pathologic stage, and tumor size. Moreover, patients with lower levels of MEG3 expression had a relatively poor prognosis. Overexpression of MEG3 decreased NSCLC cells proliferation and induced apoptosis in vitro and impeded tumorigenesis in vivo. MDM2 and p53 protein levels were affected by MEG3 over-expression in vitro.ConclusionsOur findings indicate that MEG3 is significantly down-regulated in NSCLC tissues that could be affected by DNA methylation, and regulates NSCLC cell proliferation and apoptosis, partially via the activition of p53. Thus, MEG3 may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC intervention.

Project description:Diffuse large B‑cell lymphoma (DLBCL) remains difficult to treat clinically due to its highly aggressive characteristics. Insulin‑like growth factor 2 mRNA‑binding protein 2 (IGF2BP2) and 5'‑nucleotidase domain‑containing 2 (NT5DC2) have been suggested as potential regulators in numerous types of cancer. The present study aimed to determine whether downregulation of IGF2BP2 and NT5DC2 suppresses cell proliferation, and induces cell cycle arrest and apoptosis in DLBCL cells by regulating the p53 signaling pathway. The expression levels of IGF2BP2 and NT5DC2 in DLBCL cells were determined by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. Transfection of cells with IGF2BP2 overexpressing plasmids and NT5DC2 interference plasmids was performed, and the efficacy of transfection was confirmed by RT‑qPCR and western blot analysis. The viability, proliferation, cell cycle progression and apoptosis of DLBCL cells were analyzed by Cell Counting Kit‑8 assay, 5‑bromo‑2‑deoxyuridine staining and flow cytometry. RNA pull‑down and immunoprecipitation assays were used to verify the binding of IGF2BP2 and NT5DC2. The expression levels of apoptosis, cell cycle and p53 pathway‑associated proteins were determined by western blotting. The results revealed that NT5DC2 expression was increased in DLBCL cell lines and was the highest in OCI‑Ly7 cells. IGF2BP2 expression was also increased in OCI‑Ly7 cells and IGF2BP2 bound to NT5DC2. Knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells, which was reversed by upregulation of IGF2BP2. In addition, knockdown of NT5DC2 increased the expression of p53 and p21, but suppressed the expression of proliferating cell nuclear antigen, CDK4 and cyclin D1; these effects were reversed by upregulation of IGF2BP2. In conclusion, knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells by regulating the p53 signaling pathway and these effects were reversed by upregulation of IGF2BP2.

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

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

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