Peptides Targeting RNA m6A Methylations Influence the Viability of Cancer Cells

An RNA-binding peptide inhibits the binding and demethylase activity of the fat mass obesity-associated protein, FTO. The mtp1 peptide also decreases the viability of several cancer cell lines while maintaining low levels of cytotoxicity against non-cancerous cells.

Abstract

N6-methyladenosine (m⁶A) is the most abundant nucleotide modification observed in eukaryotic mRNA. Changes in m⁶A levels in transcriptome are tightly correlated to expression levels of m⁶A methyltransferases and demethylases. Abnormal expression levels of methyltransferases and demethylases are observed in various diseases and health conditions such as cancer, male infertility, and obesity. This research explores the efficacy of m⁶A-modified RNA as an anticancer drug target. We discovered a 12-mer peptide that binds specifically to m⁶A-modified RNA using phage display experiments. Our fluorescence-based assays illustrate the selected peptide binds to methylated RNA with lower micromolar affinity and inhibit the binding of protein FTO, a demethylase enzyme specific to m⁶A modification. When cancer cell lines were treated with mtp1, it led to an increase in m⁶A levels and a decrease in cell viability. Hence our results illustrate the potential of mtp1 to be developed as a drug for cancer.

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