title: Three-dimensional cell growth confers radioresistance by chromatin density modification.
abstract: Cell shape and architecture are determined by cell-extracellular matrix interactions and have profound effects on cellular behavior, chromatin condensation, and tumor cell resistance to radiotherapy and chemotherapy. To evaluate the role of chromatin condensation for radiation cell survival, tumor cells grown in three-dimensional (3D) cell cultures as xenografts and monolayer cell cultures were compared. Here, we show that increased levels of heterochromatin in 3D cell cultures characterized by histone H3 deacetylation and induced heterochromatin protein 1alpha expression result in increased radiation survival and reduced numbers of DNA double strand breaks (DSB) and lethal chromosome aberrations. Intriguingly, euchromatin to heterochromatin-associated DSBs were equally distributed in irradiated 3D cell cultures and xenograft tumors, whereas irradiated monolayer cultures showed a 2:1 euchromatin to heterochromatin DSB distribution. Depletion of histone deacetylase (HDAC) 1/2/4 or application of the class I/II pharmacologic HDAC inhibitor LBH589 induced moderate or strong chromatin decondensation, respectively, which was translated into cell line-dependent radiosensitization and, in case of LBH589, into an increased number of DSBs. Neither growth conditions nor HDAC modifications significantly affected the radiation-induced phosphorylation of the important DNA repair protein ataxia telangiectasia mutated. Our data show an interrelation between cell morphology and cellular radiosensitivity essentially based on chromatin organization. Understanding the molecular mechanisms by which chromatin structure influences the processing of radiation-induced DNA lesions is of high relevance for normal tissue protection and optimization of cancer therapy.
authors.affiliation: OncoRay-Center for Radiation Research in Oncology, Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Storch
authors.forename: Iris
authors.initials: I
authors.lastname: Eke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Christian
authors.initials: C
authors.lastname: Richter
authors.forename: Kerstin
authors.initials: K
authors.lastname: Becker
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000378:metabolism; D048430:Cell Shape; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D022041:Euchromatin / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006570:Heterochromatin / Q000502:physiology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D025521:Tumor Suppressor Proteins; D000090266:Chromobox Protein Homolog 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D006655:Histone Deacetylases