Impact of DNA and RNA methylation on radiobiology and cancer progression

Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and radioresistance is highly associated with poor prognosis and risk of recurrence. Elucidation of the biological characteristics of radioresistance and development of effective prognostic markers to guide clinical decision making clearly remain an urgent medical requirement. In tumorigenic and radioresistant cancer cell populations, phenotypic switch is observed during the course of irradiation treatment, which is associated with both stable genetic and epigenetic changes. While the importance of epigenetic changes is widely accepted, the irradiation-triggered specific epigenetic alterations at the molecular level are incompletely defined. The present review provides a summary of current studies on the molecular functions of DNA and RNA m⁶A methylation, the key epigenetic mechanisms involved in regulating the expression of genetic information, in resistance to irradiation and cancer progression. We additionally discuss the effects of DNA methylation and RNA N⁶-methyladenosine (m⁶A) of specific genes in cancer progression, recurrence, and radioresistance. As epigenetic alterations could be reversed by drug treatment or inhibition of specific genes, they are also considered potential targets for anticancer therapy and/or radiotherapy sensitizers. The mechanisms of irradiation-induced alterations in DNA and RNA m⁶A methylation, and ways in which this understanding can be applied clinically, including utilization of methylation patterns as prognostic markers for cancer radiotherapy and their manipulation for anticancer therapy or use as radiotherapy sensitizers, have been further discussed.