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.