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Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage

BACKGROUND: Long non‐coding RNAs (lncRNAs) play a crucial role in tumour initiation and progression. However, little is known about their contributions to p53‐related bladder cancer (BC) inhibition. METHODS: By using high‐throughput sequencing, we screened the expression profiles of lncRNAs in BC an...

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Autores principales: Li, Juan, Wang, Yifan, Zhang, Xinya, Yang, Xuemei, Qi, Qiuchen, Mi, Qi, Feng, Maoxiao, Wang, Yunshan, Wang, Chuanxin, Li, Peilong, Du, Lutao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9797767/
https://www.ncbi.nlm.nih.gov/pubmed/36578176
http://dx.doi.org/10.1002/ctm2.1149
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author Li, Juan
Wang, Yifan
Zhang, Xinya
Yang, Xuemei
Qi, Qiuchen
Mi, Qi
Feng, Maoxiao
Wang, Yunshan
Wang, Chuanxin
Li, Peilong
Du, Lutao
author_facet Li, Juan
Wang, Yifan
Zhang, Xinya
Yang, Xuemei
Qi, Qiuchen
Mi, Qi
Feng, Maoxiao
Wang, Yunshan
Wang, Chuanxin
Li, Peilong
Du, Lutao
author_sort Li, Juan
collection PubMed
description BACKGROUND: Long non‐coding RNAs (lncRNAs) play a crucial role in tumour initiation and progression. However, little is known about their contributions to p53‐related bladder cancer (BC) inhibition. METHODS: By using high‐throughput sequencing, we screened the expression profiles of lncRNAs in BC and adjacent non‐tumour tissues. The roles of a novel lncRNA, named LNPPS [a lncRNA for programmed cell death 5 (PDCD5) and p53 stability], were determined by gain‐ and loss‐of‐function assays. RNA pull‐down followed by mass spectrometry analysis, RNA immunoprecipitation assays and other immunoprecipitation assays were performed to reveal the interactions among LNPPS, PDCD5 and p53, and the regulatory effect of LNPPS on the complex ubiquitination network comprising PDCD5, p53 and mouse double minute 2 homologue (MDM2). RESULTS: LNPPS was downregulated in BC and markedly inhibited the viability of BC cells by inducing PDCD5/p53‐related apoptosis in vivo and in vitro. Mechanistically, LNPPS, serving as a scaffold, connected PDCD5 and p53 with nucleotides (nt) located at 121‒251 nt and 251‒306 nt of LNPPS, respectively. This process allowed LNPPS to protect PDCD5 from proteasomal degradation by blocking its K20 site ubiquitination. On the other hand, the increased interaction between PDCD5 and p53 displaced p53 from the MDM2‒p53 ubiquitination complex, resulting in an increase in p53 expression and related apoptosis levels. Moreover, LNPPS could induce the accumulation of PDCD5 and p53 in the nucleus and exert a synergistic effect on the prevention of protein degradation. In addition, we confirmed that the downregulation of LNPPS in BC was mediated by the decreased N6‐methyladenosine (m(6)A) modification. CONCLUSION: Our findings highlight a novel cross‐talk between LNPPS and the PDCD5/p53/MDM2 ubiquitination axis in BC development, indicating its potential as a therapeutic target for BC patients.
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spelling pubmed-97977672023-01-05 Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage Li, Juan Wang, Yifan Zhang, Xinya Yang, Xuemei Qi, Qiuchen Mi, Qi Feng, Maoxiao Wang, Yunshan Wang, Chuanxin Li, Peilong Du, Lutao Clin Transl Med Research Articles BACKGROUND: Long non‐coding RNAs (lncRNAs) play a crucial role in tumour initiation and progression. However, little is known about their contributions to p53‐related bladder cancer (BC) inhibition. METHODS: By using high‐throughput sequencing, we screened the expression profiles of lncRNAs in BC and adjacent non‐tumour tissues. The roles of a novel lncRNA, named LNPPS [a lncRNA for programmed cell death 5 (PDCD5) and p53 stability], were determined by gain‐ and loss‐of‐function assays. RNA pull‐down followed by mass spectrometry analysis, RNA immunoprecipitation assays and other immunoprecipitation assays were performed to reveal the interactions among LNPPS, PDCD5 and p53, and the regulatory effect of LNPPS on the complex ubiquitination network comprising PDCD5, p53 and mouse double minute 2 homologue (MDM2). RESULTS: LNPPS was downregulated in BC and markedly inhibited the viability of BC cells by inducing PDCD5/p53‐related apoptosis in vivo and in vitro. Mechanistically, LNPPS, serving as a scaffold, connected PDCD5 and p53 with nucleotides (nt) located at 121‒251 nt and 251‒306 nt of LNPPS, respectively. This process allowed LNPPS to protect PDCD5 from proteasomal degradation by blocking its K20 site ubiquitination. On the other hand, the increased interaction between PDCD5 and p53 displaced p53 from the MDM2‒p53 ubiquitination complex, resulting in an increase in p53 expression and related apoptosis levels. Moreover, LNPPS could induce the accumulation of PDCD5 and p53 in the nucleus and exert a synergistic effect on the prevention of protein degradation. In addition, we confirmed that the downregulation of LNPPS in BC was mediated by the decreased N6‐methyladenosine (m(6)A) modification. CONCLUSION: Our findings highlight a novel cross‐talk between LNPPS and the PDCD5/p53/MDM2 ubiquitination axis in BC development, indicating its potential as a therapeutic target for BC patients. John Wiley and Sons Inc. 2022-12-28 /pmc/articles/PMC9797767/ /pubmed/36578176 http://dx.doi.org/10.1002/ctm2.1149 Text en © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Li, Juan
Wang, Yifan
Zhang, Xinya
Yang, Xuemei
Qi, Qiuchen
Mi, Qi
Feng, Maoxiao
Wang, Yunshan
Wang, Chuanxin
Li, Peilong
Du, Lutao
Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title_full Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title_fullStr Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title_full_unstemmed Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title_short Characterisation of a novel transcript LNPPS acting as tumour suppressor in bladder cancer via PDCD5‐mediated p53 degradation blockage
title_sort characterisation of a novel transcript lnpps acting as tumour suppressor in bladder cancer via pdcd5‐mediated p53 degradation blockage
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9797767/
https://www.ncbi.nlm.nih.gov/pubmed/36578176
http://dx.doi.org/10.1002/ctm2.1149
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