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Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression
The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m(6)A levels by silencing either N(6)-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. M...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170038/ https://www.ncbi.nlm.nih.gov/pubmed/30306128 http://dx.doi.org/10.1126/sciadv.aar8263 |
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author | Panneerdoss, Subbarayalu Eedunuri, Vijay K. Yadav, Pooja Timilsina, Santosh Rajamanickam, Subapriya Viswanadhapalli, Suryavathi Abdelfattah, Nourhan Onyeagucha, Benjamin C. Cui, Xiadong Lai, Zhao Mohammad, Tabrez A. Gupta, Yogesh K. Huang, Tim Hui-Ming Huang, Yufei Chen, Yidong Rao, Manjeet K. |
author_facet | Panneerdoss, Subbarayalu Eedunuri, Vijay K. Yadav, Pooja Timilsina, Santosh Rajamanickam, Subapriya Viswanadhapalli, Suryavathi Abdelfattah, Nourhan Onyeagucha, Benjamin C. Cui, Xiadong Lai, Zhao Mohammad, Tabrez A. Gupta, Yogesh K. Huang, Tim Hui-Ming Huang, Yufei Chen, Yidong Rao, Manjeet K. |
author_sort | Panneerdoss, Subbarayalu |
collection | PubMed |
description | The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m(6)A levels by silencing either N(6)-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m(6)A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor–β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m(6)A modifications, as altered m(6)A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m(6)A status of target genes by controlling each other’s expression and by inhibiting m(6)A reader YTHDF3 (YTH N(6)-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m(6)A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m(6)A in cancer and shows that the collaboration among writers-erasers-readers sets up the m(6)A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m(6)A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression. |
format | Online Article Text |
id | pubmed-6170038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61700382018-10-10 Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression Panneerdoss, Subbarayalu Eedunuri, Vijay K. Yadav, Pooja Timilsina, Santosh Rajamanickam, Subapriya Viswanadhapalli, Suryavathi Abdelfattah, Nourhan Onyeagucha, Benjamin C. Cui, Xiadong Lai, Zhao Mohammad, Tabrez A. Gupta, Yogesh K. Huang, Tim Hui-Ming Huang, Yufei Chen, Yidong Rao, Manjeet K. Sci Adv Research Articles The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m(6)A levels by silencing either N(6)-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m(6)A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor–β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m(6)A modifications, as altered m(6)A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m(6)A status of target genes by controlling each other’s expression and by inhibiting m(6)A reader YTHDF3 (YTH N(6)-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m(6)A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m(6)A in cancer and shows that the collaboration among writers-erasers-readers sets up the m(6)A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m(6)A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression. American Association for the Advancement of Science 2018-10-03 /pmc/articles/PMC6170038/ /pubmed/30306128 http://dx.doi.org/10.1126/sciadv.aar8263 Text en Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Panneerdoss, Subbarayalu Eedunuri, Vijay K. Yadav, Pooja Timilsina, Santosh Rajamanickam, Subapriya Viswanadhapalli, Suryavathi Abdelfattah, Nourhan Onyeagucha, Benjamin C. Cui, Xiadong Lai, Zhao Mohammad, Tabrez A. Gupta, Yogesh K. Huang, Tim Hui-Ming Huang, Yufei Chen, Yidong Rao, Manjeet K. Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title | Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title_full | Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title_fullStr | Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title_full_unstemmed | Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title_short | Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression |
title_sort | cross-talk among writers, readers, and erasers of m(6)a regulates cancer growth and progression |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170038/ https://www.ncbi.nlm.nih.gov/pubmed/30306128 http://dx.doi.org/10.1126/sciadv.aar8263 |
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