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

Subbarayalu Panneerdoss, Vijay K. Eedunuri, Pooja Yadav, Santosh Timilsina, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Nourhan Abdelfattah, Benjamin C. Onyeagucha, Xiadong Cui, Zhao Lai, Tabrez A. Mohammad, Yogesh K Gupta, Hui-ming Huang, Yufei Huang, Yidong Chen, Manjeet K Rao

Research output: Contribution to journalArticle

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Abstract

The importance of RNA methylation in biological processes is an emerging focus of 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-b 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 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.

Original languageEnglish (US)
Article numbereaar8263
JournalScience advances
Volume4
Issue number10
DOIs
StatePublished - Oct 3 2018

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Methyltransferases
Growth
Genes
Neoplasms
RNA
RNA Sequence Analysis
Biological Phenomena
Epithelial-Mesenchymal Transition
RNA-Binding Proteins
RNA Stability
Transforming Growth Factors
Immunoprecipitation
Adenosine
Methylation
Cell Cycle
Apoptosis
Gene Expression
Hypoxia

ASJC Scopus subject areas

  • General

Cite this

Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., Viswanadhapalli, S., ... Rao, M. K. (2018). Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. Science advances, 4(10), [eaar8263]. https://doi.org/10.1126/sciadv.aar8263

Cross-talk among writers, readers, and erasers of m6A 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, Hui-ming; Huang, Yufei; Chen, Yidong; Rao, Manjeet K.

In: Science advances, Vol. 4, No. 10, eaar8263, 03.10.2018.

Research output: Contribution to journalArticle

Panneerdoss, S, Eedunuri, VK, Yadav, P, Timilsina, S, Rajamanickam, S, Viswanadhapalli, S, Abdelfattah, N, Onyeagucha, BC, Cui, X, Lai, Z, Mohammad, TA, Gupta, YK, Huang, H, Huang, Y, Chen, Y & Rao, MK 2018, 'Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression', Science advances, vol. 4, no. 10, eaar8263. https://doi.org/10.1126/sciadv.aar8263
Panneerdoss S, Eedunuri VK, Yadav P, Timilsina S, Rajamanickam S, Viswanadhapalli S et al. Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. Science advances. 2018 Oct 3;4(10). eaar8263. https://doi.org/10.1126/sciadv.aar8263
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, Hui-ming ; Huang, Yufei ; Chen, Yidong ; Rao, Manjeet K. / Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. In: Science advances. 2018 ; Vol. 4, No. 10.
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AU - Lai, Zhao

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