Asunto(s)
Epigénesis Genética/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Tolerancia a Radiación/genética , Retinal-Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Animales , Western Blotting , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Hibridación Genómica Comparativa , Metilación de ADN/efectos de la radiación , Citometría de Flujo , Xenoinjertos , Histonas/genética , Histonas/efectos de la radiación , Humanos , Masculino , Ratones , Ratones Desnudos , Microscopía Fluorescente , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/efectos de la radiación , Retinal-Deshidrogenasa/efectos de la radiaciónRESUMEN
Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations. Cancer Res; 76(9); 2637-51. ©2016 AACR.
