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Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.

ABSTRACT: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a broadly expressed lncRNA involved in many aspects of cellular processes. To further delineate the underlying molecular mechanism, we employed a high-throughput strategy to characterize the interacting proteins of MALAT1 by combining RNA pull-down, quantitative proteomics, bioinformatics, and experimental validation. Our approach identified 127 potential MALAT1-interacting proteins and established a highly connected MALAT1 interactome network consisting of 788 connections. Gene ontology annotation and network analysis showed that MALAT1 was highly involved in five biological processes: RNA processing; gene transcription; ribosomal proteins; protein degradation; and metabolism regulation. The interaction between MALAT1 and depleted in breast cancer 1 (DBC1) was validated using RNA pull-down and RNA immunoprecipitation. Further mechanistic studies reveal that MALAT1 binding competes with the interaction between sirtuin1 (SIRT1) and DBC1, which then releases SIRT1 and enhances its deacetylation activity. Consequently, the deacetylation of p53 reduces the transcription of a spectrum of its downstream target genes, promotes cell proliferation and inhibits cell apoptosis. Our results uncover a novel mechanism by which MALAT1 regulates the activity of p53 through the lncRNA-protein interaction.

SUBMITTER: Chen R

PROVIDER: S-EPMC5622371 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Prostate cancer (PCa) is one of the principal causes of cancer‑related death worldwide. The roles and mechanisms of long non‑coding RNA (lncRNA) involved in the development of PCa remain incompletely understood. The present study aimed to investigate the role and mechanism of lncRNA in PCa tumorigenesis. In the present study, lncRNA cancer susceptibility candidate 11 (CASC11) was revealed to be a crucial regulator of PCa progression. The expression profiles of CASC11 in PCa were identified through analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets, and validated in human PCa specimens and cell lines. Gain‑ and loss‑of‑function assays were utilized to explore the biological role of CASC11 in PCa initiation and progression. RNA‑sequencing, RNA pull‑down and RNA immunoprecipitation analyses were used to explore potential mechanisms with which CASC11 may be associated. Rescue experiments were further conducted to confirm this association. The present results revealed that CASC11 was dominantly distributed in the nuclei of PCa cells, and was highly expressed in PCa tissues and cells. Overexpression of CASC11 was markedly associated with increased tumor proliferation and migratory ability. Functionally, decreased proliferation and migration, as well as inhibited xenograft tumor growth, were observed in CASC11‑silenced PCa cells, whereas the opposite effects were detected in CASC11‑overexpressing cells. Mechanistically, CASC11 promoted progression of the cell cycle and competitively interacted with Y‑box binding protein 1 (YBX1) to block the p53 pathway. Given this, poly (β‑amino ester) (PBAE)/small interfering RNA‑CASC11 (si‑CASC11) nanoparticles were applied to inhibit CASC11 expression and enhance the antitumor effect in vivo. The results revealed that PBAE/si‑CASC11 nanoparticles augmented the antitumor efficacy of CASC11 knockdown in vivo. In conclusion, the present study suggested that CASC11 may regulate PCa progression and elucidated a novel CASC11/YBX1/p53 signaling axis, providing a potential lncRNA‑directed therapeutic strategy particularly for the treatment of patients with PCa.

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Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.

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