title: An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells.
abstract: 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.
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Peitzsch
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Cojoc
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Hein
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Kurth
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mäbert
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Trautmann
authors.affiliation: Institute of Clinical Genetics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. German Cancer Consortium (DKTK), Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
authors.affiliation: Institute of Clinical Genetics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. German Cancer Consortium (DKTK), Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.affiliation: Department of Urology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. German Cancer Consortium (DKTK), Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiation Oncology, Dresden, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: National Cancer Institute, Kyiv, Ukraine.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Stakhovsky
authors.affiliation: Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv, Ukraine.
authors.forename: Gennady D
authors.initials: GD
authors.lastname: Telegeev
authors.affiliation: Department of Urology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novotny
authors.affiliation: Department of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Marieta
authors.initials: M
authors.lastname: Toma
authors.affiliation: Department of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Muders
authors.affiliation: Department of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.affiliation: YCR Cancer Research Unit, Department of Biology, University of York, York, United Kingdom.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Frame
authors.affiliation: YCR Cancer Research Unit, Department of Biology, University of York, York, United Kingdom.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. German Cancer Consortium (DKTK), Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiation Oncology, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. German Cancer Consortium (DKTK), Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiation Oncology, Dresden, Germany. Anna.Dubrovska@OncoRay.de.
authors.forename: Anna
authors.initials: A
authors.lastname: Dubrovska
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation / Q000528:radiation effects; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D064593:Heterografts; D006657:Histones / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy; D050697:Retinal Dehydrogenase / Q000235:genetics* / Q000528:radiation effects
chemical_list: D006657:Histones; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase