Science Advances: Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression
Subbarayalu Panneerdoss1,2,*, Vijay K. Eedunuri1,2,*, Pooja Yadav1,2, Santosh Timilsina1,2, Subapriya Rajamanickam2,3, Suryavathi Viswanadhapalli4, View ORCID ProfileNourhan Abdelfattah1,2, Benjamin C. Onyeagucha1,2, View ORCID ProfileXiadong Cui5, Zhao Lai2, View ORCID ProfileTabrez A. Mohammad2, View ORCID ProfileYogesh K. Gupta2,6, Tim Hui-Ming uang3, Yufei Huang5,†, View ORCID ProfileYidong Chen2,7,† and View ORCID ProfileManjeet K. Rao1,2,†
Abstract
The importance of RNA methylation in biological processes is an emerging focus of the investigation. We report that altering m6A levels by silencing either N6-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 m6A 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 m6A modifications, as altered m6A 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 m6A status of target genes by controlling each other’s expression and by inhibiting m6A reader YTHDF3 (YTH N6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with the 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 m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.
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