RESUMO
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.
Assuntos
Epigênese Genética/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias da Próstata/genética , Tolerância a Radiação/genética , Retinal Desidrogenase/genética , Família Aldeído Desidrogenase 1 , Animais , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Hibridização Genômica Comparativa , Metilação de DNA/efeitos da radiação , Citometria de Fluxo , Xenoenxertos , Histonas/genética , Histonas/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/efeitos da radiação , Radioterapia , Retinal Desidrogenase/efeitos da radiaçãoRESUMO
Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial-mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH(+) and ALDH(-) cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/ß-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of ß-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH(+) tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH(+) cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy.
