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Updated: Jul 31, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
Advances in targeting RNA modifications for anticancer therapy
Monica M Pomaville1, Chuan He2
1Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA; Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
Abstract:
Numerous strategies are employed by cancer cells to control gene expression and facilitate tumorigenesis. In the study of epitranscriptomics, a diverse set of modifications to RNA represent a new player of gene regulation in disease and in development. N6-methyladenosine (m6A) is the most common modification on mammalian messenger RNA and tends to be aberrantly placed in cancer. Recognized by a series of reader proteins that dictate the fate of the RNA, m6A-modified RNA could promote tumorigenesis by driving protumor gene expression signatures and altering the immunologic response to tumors. Preclinical evidence suggests m6A writer, reader, and eraser proteins are attractive therapeutic targets. First-in-human studies are currently testing small molecule inhibition against the methyltransferase-like 3 (METTL3)/methyltransferase-like 14 (METTL14) methyltransferase complex. Additional modifications to RNA are adopted by cancers to drive tumor development and are under investigation.
Insights
Cancer cells utilize RNA modifications like N-methyladenosine (m6A) for gene regulation and tumor growth. Targeting m6A proteins offers a promising therapeutic strategy for cancer treatment.
Area of Science:
- Epitranscriptomics
- Cancer Biology
- Molecular Oncology
Background:
- Cancer cells employ diverse gene expression strategies for tumorigenesis.
- RNA modifications, particularly N-methyladenosine (m6A), are emerging as key regulators in disease.
- Aberrant m6A placement in cancer influences gene expression and immune response.
Purpose of the Study:
- To investigate the role of m6A RNA modifications in cancer development.
- To explore m6A writer, reader, and eraser proteins as potential therapeutic targets.
- To highlight the significance of epitranscriptomics in oncology.
Main Methods:
- Review of preclinical evidence on m6A modification pathways.
- Analysis of m6A reader proteins' function in RNA fate determination.
- Examination of ongoing first-in-human studies targeting METTL3/METTL14 complex.
Main Results:
- m6A modification is prevalent in mammalian mRNA and dysregulated in cancer.
- m6A-modified RNA can promote tumorigenesis by altering gene expression and immune surveillance.
- m6A writer, reader, and eraser proteins are validated as potential therapeutic targets.
Conclusions:
- Epitranscriptomic modifications, especially m6A, play a critical role in cancer progression.
- Targeting the m6A machinery, including the METTL3/METTL14 complex, shows therapeutic potential.
- Further investigation into RNA modifications is crucial for developing novel cancer treatments.
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