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Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine
BACKGROUND: N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. METHODS: We analyzed the m6A status using patients samples and bone meta...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733260/ https://www.ncbi.nlm.nih.gov/pubmed/33308223 http://dx.doi.org/10.1186/s12943-020-01293-4 |
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author | Wen, Simeng Wei, Yulei Zen, Chong Xiong, Wei Niu, Yuanjie Zhao, Yu |
author_facet | Wen, Simeng Wei, Yulei Zen, Chong Xiong, Wei Niu, Yuanjie Zhao, Yu |
author_sort | Wen, Simeng |
collection | PubMed |
description | BACKGROUND: N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. METHODS: We analyzed the m6A status using patients samples and bone metastatic PDXs. Through m6A high-throughput sequencing, we identified the m6A sites on NEAT1–1 in prostate bone metastatic PDXs. Mass spec assay showed interaction among NEAT1–1, CYCLINL1 and CDK19. RNA EMSA, RNA pull-down, mutagenesis, CLIP, western blot, ChIP and ChIRP assays were used to investigate the molecular mechanisms underlying the functions of m6A on NEAT1–1. Loss-of function and rescued experiments were executed to detect the biological roles of m6A on NEAT1–1 in the PDX cell phenotypes in vivo. RESULTS: In this study, we identified 4 credible m6A sites on long ncRNA NEAT1–1. High m6A level of NEAT1–1 was related to bone metastasis of prostate cancer and m6A level of NEAT1–1 was a powerful predictor of eventual death. Transcribed NEAT1–1 served as a bridge to facility the binding between CYCLINL1 and CDK19 and promoted the Pol II ser2 phosphorylation. Importantly, depletion of NEAT1–1or decreased m6A of NEAT1–1 impaired Pol II Ser-2p level in the promoter of RUNX2. Overexpression of NEAT1–1 induced cancer cell metastasis to lung and bone; xenograft growth and shortened the survival of mice, but NEAT1–1 with m6A site mutation failed to do these. CONCLUSION: Collectively, the findings indicate that m6A on ncRNA NEAT1–1 takes critical role in regulating Pol II ser2 phosphorylation and may be novel specific target for bone metastasis cancer therapy and diagnosis. New complex CYCLINL1/CDK19/NEAT1–1 might provide new insight into the potential mechanism of the pathogenesis and development of bone metastatic prostate cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-020-01293-4. |
format | Online Article Text |
id | pubmed-7733260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-77332602020-12-14 Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine Wen, Simeng Wei, Yulei Zen, Chong Xiong, Wei Niu, Yuanjie Zhao, Yu Mol Cancer Research BACKGROUND: N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. METHODS: We analyzed the m6A status using patients samples and bone metastatic PDXs. Through m6A high-throughput sequencing, we identified the m6A sites on NEAT1–1 in prostate bone metastatic PDXs. Mass spec assay showed interaction among NEAT1–1, CYCLINL1 and CDK19. RNA EMSA, RNA pull-down, mutagenesis, CLIP, western blot, ChIP and ChIRP assays were used to investigate the molecular mechanisms underlying the functions of m6A on NEAT1–1. Loss-of function and rescued experiments were executed to detect the biological roles of m6A on NEAT1–1 in the PDX cell phenotypes in vivo. RESULTS: In this study, we identified 4 credible m6A sites on long ncRNA NEAT1–1. High m6A level of NEAT1–1 was related to bone metastasis of prostate cancer and m6A level of NEAT1–1 was a powerful predictor of eventual death. Transcribed NEAT1–1 served as a bridge to facility the binding between CYCLINL1 and CDK19 and promoted the Pol II ser2 phosphorylation. Importantly, depletion of NEAT1–1or decreased m6A of NEAT1–1 impaired Pol II Ser-2p level in the promoter of RUNX2. Overexpression of NEAT1–1 induced cancer cell metastasis to lung and bone; xenograft growth and shortened the survival of mice, but NEAT1–1 with m6A site mutation failed to do these. CONCLUSION: Collectively, the findings indicate that m6A on ncRNA NEAT1–1 takes critical role in regulating Pol II ser2 phosphorylation and may be novel specific target for bone metastasis cancer therapy and diagnosis. New complex CYCLINL1/CDK19/NEAT1–1 might provide new insight into the potential mechanism of the pathogenesis and development of bone metastatic prostate cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-020-01293-4. BioMed Central 2020-12-12 /pmc/articles/PMC7733260/ /pubmed/33308223 http://dx.doi.org/10.1186/s12943-020-01293-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Wen, Simeng Wei, Yulei Zen, Chong Xiong, Wei Niu, Yuanjie Zhao, Yu Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title | Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title_full | Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title_fullStr | Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title_full_unstemmed | Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title_short | Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine |
title_sort | long non-coding rna neat1 promotes bone metastasis of prostate cancer through n6-methyladenosine |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733260/ https://www.ncbi.nlm.nih.gov/pubmed/33308223 http://dx.doi.org/10.1186/s12943-020-01293-4 |
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