Cancer Epigenetics Beyond DNA Methylation: Role of RNA Modifications (m6A, m5C) in Tumor Initiation and Therapy Resistance
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Abstract
Epigenetic regulation has turned out to be a key factor in the formation and progression of cancer. Histone modifications and DNA methylation have traditionally been considered to be the key epigenetic processes that mediate oncogenesis. Recent discoveries, however, emphasize the importance of other types of RNA modifications, i.e. N6 -methyl adenosine (m6A) and 5 -methyl cytosine (m5C) that creates an extra layer of gene control in malignant settings. These changes are dynamically coordinated by methyltransferases, demethylases and reader proteins to mediate important facets of RNA metabolism such as splicing, stability, translation and subcellular localization. Aberrant RNA methylation is one of the largest contributory factors to tumor formation, disease pathogenesis, immune-survival, and resistance to therapy. The imbalance between m6A and m5C disrupts the regular RNA metabolism, thus promoting oncogenic signalling, stem-cell-like behaviour of cancer cells, and immune escape. Consequently, growing data suggest that the development of aberrant RNA methylation is associated with chemotherapy, radiotherapy, targeted therapy, and immunotherapy resistance. m6A/m5C perturbations activating particular molecular pathways involve increased DNA repair ability, metabolic repositioning and changed dynamics of antigen-presentation. The review summarizes the existing literature on the molecular processes controlled by m6A and m5C in cancer, and provides two summary tables one listing the canonical regulators of these RNA modifications as involved in oncogenesis, and the other listing their role in therapeutic resistance. . Lastly, we touch on the future clinical uses of epitranscriptomic data in cancer, and how novel biomarkers and targeted therapies can improve the patient outcomes.
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