In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 4, No. 10 ( 2018-10-05)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2375-2548
DOI:
10.1126/sciadv.aar8263
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2018
detail.hit.zdb_id:
2810933-8
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