An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells.

Radiation therapy 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 survive radiation therapy, 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 research. 2016 Mar 16 [Epub ahead of print]

Claudia Peitzsch, Monica Cojoc, Linda Hein, Ina Kurth, Katrin Mӓbert, Franziska Trautmann, Barbara Klink, Evelin Schrock, Manfred P Wirth, Mechthild Krause, Eduard A Stakhovsky, Gennady D Telegeev, Vladimir Novotny, Marieta Ioana Toma, Michael Muders, Gustavo B Baretton, Fiona M Frame, Norman J Maitland, Michael Baumann, Anna Dubrovska

OncoRay, OncoRay-National Center for Radiation Research in Oncology, TU Dresden., OncoRay, OncoRay-National Center for Radiation Research in Oncology, TU Dresden., Medical faculty, OncoRay, TU Dresden., OncoRay, OncoRay-National Center for Radiation Research in Oncology, TU Dresden., OncoRay, OncoRay-National Center for Radiation Research in Oncology, TU Dresden., OncoRay, OncoRay-National Center for Radiation Research in Oncology, TU Dresden., Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus., Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Institute of Clinical Genetics., Department of Urology, Dresden University of Technology., Department of Radiation Oncology, OncoRay National Center for Radiation Research, DKFZ HD and DKTK DD, Fac.Med. and Univ. Hosp. CGC, TU Dresden; OncoRay - Natl.C.RadRes DD, Helmholtz-Zentrum Dresden - Rossendorf, NCT DD., Department of tumors of the abdominal cavity and retroperitoneal space, National Cancer Institute., Molecular Genetics, Institute of Molecular Biology and Genetics NAS of Ukraine., Department of Urology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden., Institute of Pathology, Dresden Technical University., Institue of Pathology, University Hospital., Department of Pathology, TU Dresden., Department of Biology, University of York., Yorkshire Cancer Research Unit, Department of Biology, University of York., Radiation oncology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden., Medical faculty, OncoRay, TU Dresden .