Epigenetics as a determinant of radiation response in cancer

Radiation therapy is a cornerstone of modern cancer treatment. Treatment is based on depositing focal radiation to the tumor to inhibit cell growth, proliferation and metastasis, and to promote the death of cancer cells. In addition, radiation also affects non-tumor cells in the tumor microenvironmental (TME). Radiation resistance of the tumor cells is the most common cause of treatment failure, allowing survival of cancer cell and subsequent tumor growing. Molecular radioresistance comprises genetic and epigenetic characteristics inherent in cancer cells, or characteristics acquired after exposure to radiation. Furthermore, cancer stem cells (CSCs) and non-tumor cells into the TME as stromal and immune cells have a role in promoting and maintaining radioresistant tumor phenotypes. Different regulatory molecules and pathways distinctive of radiation resistance include DNA repair, survival signaling and cell death pathways. Epigenetic mechanisms are one of the most relevant events that occur after radiotherapy to regulate the expression and function of key genes and proteins in the differential radiation-response. This article reviews recent data on the main molecular mechanisms and signaling pathways related to the biological response to radiotherapy in cancer; highlighting the epigenetic control exerted by DNA methylation, histone marks, chromatin remodeling and m6A RNA methylation on gene expression and activation of signaling pathways related to radiation therapy response.