Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells

Sianadh Dunn, Olivia Lombardi, Radoslaw Lukoszek, Victoria Cowling (Lead / Corresponding author)

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    16 Citations (Scopus)
    302 Downloads (Pure)

    Abstract

    Basic mechanisms in gene expression are currently being investigated as targets in cancer therapeutics. One such fundamental process is the addition of the cap to pre-mRNA, which recruits mediators of mRNA processing and translation initiation. Maturation of the cap involves mRNA cap guanosine N-7 methylation, catalysed by RNMT (RNA guanine-7 methyltransferase). In a panel of breast cancer cell lines, we investigated whether all are equivalently dependent on RNMT for proliferation. When cellular RNMT activity was experimentally reduced by 50%, the proliferation rate of non-transformed mammary epithelial cells was unchanged, whereas a subset of breast cancer cell lines exhibited reduced proliferation and increased apoptosis. Most of the cell lines which exhibited enhanced dependency on RNMT harboured oncogenic mutations in PIK3CA, which encodes the p110α subunit of PI3Kα. Conversely, all cell lines insensitive to RNMT depletion expressed wild-type PIK3CA. Expression of oncogenic PIK3CA mutants, which increase PI3K p110α activity, was sufficient to increase dependency on RNMT. Conversely, inhibition of PI3Kα reversed dependency on RNMT, suggesting that PI3Kα signalling is required. Collectively, these findings provide evidence to support RNMT as a therapeutic target in breast cancer and suggest that therapies targeting RNMT would be most valuable in a PIK3CA mutant background.

    Original languageEnglish
    Article number190052
    Pages (from-to)1-15
    Number of pages15
    JournalOpen Biology
    Volume9
    Issue number4
    Early online date17 Apr 2019
    DOIs
    Publication statusPublished - Apr 2019

    Keywords

    • PI3Kα
    • PIK3CA
    • RNMT
    • breast cancer
    • cell proliferation
    • mRNA cap

    ASJC Scopus subject areas

    • General Neuroscience
    • Immunology
    • General Biochemistry,Genetics and Molecular Biology

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