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PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer

PLA2G16 is a member of the phospholipase family that catalyses the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. In the current study, we explored the functional role of PLA2G16 in pancreatic adenocarcinoma (PAAD) and the genetic/epigenetic alteratio...

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Autores principales: Xia, Wei, Bai, Hansong, Deng, Ying, Yang, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686977/
https://www.ncbi.nlm.nih.gov/pubmed/32985124
http://dx.doi.org/10.1111/jcmm.15832
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author Xia, Wei
Bai, Hansong
Deng, Ying
Yang, Yi
author_facet Xia, Wei
Bai, Hansong
Deng, Ying
Yang, Yi
author_sort Xia, Wei
collection PubMed
description PLA2G16 is a member of the phospholipase family that catalyses the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. In the current study, we explored the functional role of PLA2G16 in pancreatic adenocarcinoma (PAAD) and the genetic/epigenetic alterations leading to its dysregulation. Bioinformatic analysis was performed using data from The Cancer Genome Atlas (TCGA), Genotype‐Tissue Expression (GTEx) and the Human Protein Atlas (HPA). Then, PANC‐1 and MIA‐PaCa‐2 cells harbouring TP53 mutations were used for cellular and animal studies. Results showed that PL2G16 expression was significantly up‐regulated in PAAD tissue and was associated with unfavourable survival. PLA2G16 inhibition suppressed pancreatic cell growth in vitro and in vivo and also inhibited aerobic glycolysis. Bioinformatic analysis indicated that KLF5 was positively correlated with PLA2G16 expression in PAAD tumours with TP53 mutation. TP53 or KLF5 inhibition significantly reduced PLA2G16 expression at both mRNA and protein levels. Dual‐luciferase and chromatin Immunoprecipitation‐quantitative polymerase chain reaction assays showed that KLF5 directly bound to the PLA2G16 promoter and activated its transcription. Co‐immunoprecipitation assay indicated that mutant p53 had a physical interaction with KLF5. Inhibition of mutant p53 impaired the transcriptional activating effects of KLF5. In PAAD cases in TCGA, PLA2G16 expression was positively correlated with its copy number (Pearson's r = 0.51, P < 0.001), but was strongly and negatively correlated with the methylation level of cg09518969 (Pearson's r = −0.64, P < 0.001), a 5’‐cytosine‐phosphodiester bond‐guanine‐3’ site within its gene locus. In conclusion, this study revealed a novel mutant p53/KLF5‐PLA2G16 regulatory axis on tumour growth and glycolysis in PAAD.
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spelling pubmed-76869772020-12-03 PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer Xia, Wei Bai, Hansong Deng, Ying Yang, Yi J Cell Mol Med Original Articles PLA2G16 is a member of the phospholipase family that catalyses the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. In the current study, we explored the functional role of PLA2G16 in pancreatic adenocarcinoma (PAAD) and the genetic/epigenetic alterations leading to its dysregulation. Bioinformatic analysis was performed using data from The Cancer Genome Atlas (TCGA), Genotype‐Tissue Expression (GTEx) and the Human Protein Atlas (HPA). Then, PANC‐1 and MIA‐PaCa‐2 cells harbouring TP53 mutations were used for cellular and animal studies. Results showed that PL2G16 expression was significantly up‐regulated in PAAD tissue and was associated with unfavourable survival. PLA2G16 inhibition suppressed pancreatic cell growth in vitro and in vivo and also inhibited aerobic glycolysis. Bioinformatic analysis indicated that KLF5 was positively correlated with PLA2G16 expression in PAAD tumours with TP53 mutation. TP53 or KLF5 inhibition significantly reduced PLA2G16 expression at both mRNA and protein levels. Dual‐luciferase and chromatin Immunoprecipitation‐quantitative polymerase chain reaction assays showed that KLF5 directly bound to the PLA2G16 promoter and activated its transcription. Co‐immunoprecipitation assay indicated that mutant p53 had a physical interaction with KLF5. Inhibition of mutant p53 impaired the transcriptional activating effects of KLF5. In PAAD cases in TCGA, PLA2G16 expression was positively correlated with its copy number (Pearson's r = 0.51, P < 0.001), but was strongly and negatively correlated with the methylation level of cg09518969 (Pearson's r = −0.64, P < 0.001), a 5’‐cytosine‐phosphodiester bond‐guanine‐3’ site within its gene locus. In conclusion, this study revealed a novel mutant p53/KLF5‐PLA2G16 regulatory axis on tumour growth and glycolysis in PAAD. John Wiley and Sons Inc. 2020-09-27 2020-11 /pmc/articles/PMC7686977/ /pubmed/32985124 http://dx.doi.org/10.1111/jcmm.15832 Text en © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Xia, Wei
Bai, Hansong
Deng, Ying
Yang, Yi
PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title_full PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title_fullStr PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title_full_unstemmed PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title_short PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
title_sort pla2g16 is a mutant p53/klf5 transcriptional target and promotes glycolysis of pancreatic cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686977/
https://www.ncbi.nlm.nih.gov/pubmed/32985124
http://dx.doi.org/10.1111/jcmm.15832
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