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Long noncoding RNA PANDAR blocks CDKN1A gene transcription by competitive interaction with p53 protein in gastric cancer.

ABSTRACT: Emerging evidence indicates that lncRNAs play important roles in cancer tumourigenesis and could be used as potential diagnostic biomarkers or therapeutic targets. However, the clinical significance and molecular mechanism of lncRNAs in gastric cancer (GC) is still unclear. The aim of this study was to explore the expression and role of lncRNAs in GC. The relative expression level of lncRNAs in GC samples was examined by an lncRNA microarray analysis, northern blot analysis and qRT-PCR analysis. A Kaplan-Meier survival analysis and univariate and multivariate Cox proportional hazards models were performed to evaluate the clinical and prognostic significance of PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) in GC patients. The binding activity of PANDAR with the p53 protein was analysed by an RNA immunoprecipitation analysis and RNA pull-down analysis. The depletion of PANDAR was conducted using the CRISPR/Cas9 system for PANDAR. The biological functions of PANDAR in GC cells were determined both in vitro and in vivo. Upregulated PANDAR in GC patients was positively correlated with increased tumour size, advanced TNM classification and a poor survival rate in GC patients. The ROC curves identified that the PANDAR level was a marker for discriminating the early-stage tumour group from the healthy group, the metastasis group from the non-metastasis group and the chemoresistance group from the chemosensitive group in GC patients. As a target, the CDKN1A gene was successfully downregulated by PANDAR. PANDAR controlled the transcription of the CDKN1A gene by competitively binding with p53 protein. In combination with a p53 activator (nutlin3), the knockout of PANDAR by CRISPR/Cas9 technology synergistically inhibited GC tumour growth in vivo. Our results suggest that the PANDAR is a powerful diagnostic and therapeutic marker for patients with GC and, combined with other chemotherapeutics, may have distinct antitumour effects.

SUBMITTER: Liu J

PROVIDER: S-EPMC5833854 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Long noncoding RNA PANDAR blocks CDKN1A gene transcription by competitive interaction with p53 protein in gastric cancer.

Liu Jun J Ben Qiwen Q Lu Eryi E He Xiangyi X Yang Xiaoqun X Ma Jun J Zhang Wen W Wang Zhiming Z Liu Tianshu T Zhang Jianjun J Wang Hongxia H

Cell death & disease 20180207 2

Emerging evidence indicates that lncRNAs play important roles in cancer tumourigenesis and could be used as potential diagnostic biomarkers or therapeutic targets. However, the clinical significance and molecular mechanism of lncRNAs in gastric cancer (GC) is still unclear. The aim of this study was to explore the expression and role of lncRNAs in GC. The relative expression level of lncRNAs in GC samples was examined by an lncRNA microarray analysis, northern blot analysis and qRT-PCR analysis. ...[more]

PMID: 29416011

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Project description:About 50% of human cancers across the globe arise due to a mutation in the p53 gene which gives rise to its functional inactive form, and in the rest of the cancer the efficacy of active p53 (wild-type) is hindered by MDM2-mediated degradation. Breakdown of the p53-MDM2 association may constitute an effective strategy to stimulate or reinstate the activity of wild type p53, thereby reviving the p53 tumor suppressor capability. S100A1 has been revealed to associate with the N-terminal domain of MDM2 and p53 protein. We utilized NMR spectroscopy to study the interface amongst the S100A1 and N-terminal domain of MDM2. Additionally, the S100A1-MDM2 complex generated through the HADDOCK program was then superimposed with the p53 (peptide) -MDM2 complex reported earlier. The overlay indicated that a segment of S100A1 could block the interaction of p53 (peptide) -MDM2 complex significantly. To further justify our assumption, we performed HSQC-NMR titration for the S100A1 and p53 N-terminal domain (p53-TAD). The data obtained indicated that the S100A1 segment comprising nearly 17 residues have some common residues that interact with both MDM2 and p53-TAD. Further, we synthesized the 17-residue peptide derived from the S100A1 protein and attached it to the cell-penetrating HIV-TAT peptide. The HSQC-NMR competitive binding experiment revealed that Peptide 1 could successfully interfere with the p53-MDM2 interaction. Furthermore, functional effects of the peptide was validated in cancer cells. The results showed that Peptide 1 effectively inhibited cell proliferation, and increased the protein levels of p53 and its downstream p21 in MCF-7 cells. Treatment of Peptide 1 resulted in cell cycle arrest at G2/M phase, and also induced apoptotic cell death at higher concentration. Taken together, the results suggest that disruption of the interaction of p53 and MDM2 by Peptide 1 could activate normal p53 functions, leading to cell cycle arrest and apoptotic cell death in cancer cells. We proposed here that S100A1 could influence the p53-MDM2 interaction credibly and possibly reactivates the wild type p53 pathway.

Dataset Information

Long noncoding RNA PANDAR blocks CDKN1A gene transcription by competitive interaction with p53 protein in gastric cancer.

Publications

Long noncoding RNA PANDAR blocks CDKN1A gene transcription by competitive interaction with p53 protein in gastric cancer.

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