Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression

Publication Date:
2018-10-04
Publisher:
American Association for the Advancement of Science (AAAS)
Electronic ISSN:
2375-2548
Topics:
Natural Sciences in General
Published by:
http://www.aaas.org/
_version_ 1836399063038164992
autor Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
beschreibung 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.
citation_standardnr 6341030
datenlieferant ipn_articles
feed_id 228416
feed_publisher American Association for the Advancement of Science (AAAS)
feed_publisher_url http://www.aaas.org/
insertion_date 2018-10-04
journaleissn 2375-2548
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Association for the Advancement of Science (AAAS)
quelle Science Advances
relation http://advances.sciencemag.org/cgi/content/short/4/10/eaar8263?rss=1
search_space articles
shingle_author_1 Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
shingle_author_2 Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
shingle_author_3 Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
shingle_author_4 Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
shingle_catch_all_1 Cross-talk among writers, readers, and erasers of m6A 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. 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.
Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
American Association for the Advancement of Science (AAAS)
2375-2548
23752548
shingle_catch_all_2 Cross-talk among writers, readers, and erasers of m6A 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. 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.
Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
American Association for the Advancement of Science (AAAS)
2375-2548
23752548
shingle_catch_all_3 Cross-talk among writers, readers, and erasers of m6A 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. 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.
Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
American Association for the Advancement of Science (AAAS)
2375-2548
23752548
shingle_catch_all_4 Cross-talk among writers, readers, and erasers of m6A 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. 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.
Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., Abdelfattah, N., Onyeagucha, B. C., Cui, X., Lai, Z., Mohammad, T. A., Gupta, Y. K., Huang, T. H.-M., Huang, Y., Chen, Y., Rao, M. K.
American Association for the Advancement of Science (AAAS)
2375-2548
23752548
shingle_title_1 Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
shingle_title_2 Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
shingle_title_3 Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
shingle_title_4 Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
timestamp 2025-06-30T23:37:00.339Z
titel Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
titel_suche Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
topic TA-TD
uid ipn_articles_6341030