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Abstract
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.
Highlights
Radiotherapy has been established as one of the major treatment options for patients with cancer in the clinic for over 100 years, based on the theory that cancerous regions can be destroyed with targeted ionizing radiation exposure, while normal tissue parts surrounding tumor lesions can withstand and recover after radiotherapy [1]
In contrast to data obtained from patients with glioblastoma, the methylation level of the MGMT promoter was associated with poorer prognosis or higher chance of relapse after chemo- or radiotherapy in other solid tumors, such as cervical cancer and non-small-cell lung cancer patients with brain metastasis [46,59]
Further analyses disclosed that mutations and copy number variations of m6A regulatory genes are strongly associated with the presence of TP53 mutations in Acute Myeloid Leukemia (AML) patients [158]. These results suggest that genetic alterations of m6A regulatory genes in cooperation with TP53 contribute to the pathogenesis and maintenance of AML, and provide a rationale for therapeutic targeting of METTL3 in myeloid leukemia
Summary
Radiotherapy has been established as one of the major treatment options for patients with cancer in the clinic for over 100 years, based on the theory that cancerous regions can be destroyed with targeted ionizing radiation exposure, while normal tissue parts surrounding tumor lesions can withstand and recover after radiotherapy [1]. Accumulating evidence indicates that a decisive small population of radioresistant cancer cells exhibits stem cell characteristics responsible for tumor initiation, maintenance, and progression. These cancer-initiating cells, designated cancer stem cells (CSCs), are characterized by their potent tumorigenic properties and ability to self-renew [2,3,4]. Recent studies have demonstrated crucial roles of RNA m6A methylation in both irradiation-triggered DNA damage response and radioresistance [16,17]. Elucidation of the molecular cues underlying the effects of epigenetic changes following irradiation should facilitate the design and development of effective strategies to improve the therapeutic effects of radiotherapy and prevent cancer recurrence
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