Three-Dimensional Cell Growth Confers Radioresistance by Chromatin Density Modification
Open Access
- 12 May 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (10), 3925-3934
- https://doi.org/10.1158/0008-5472.can-09-3848
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 1α 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. Cancer Res; 70(10); 3925–34. ©2010 AACR.Keywords
Other Versions
This publication has 48 references indexed in Scilit:
- Contributions of extracellular matrix signaling and tissue architecture to nuclear mechanisms and spatial organization of gene expression controlBiochimica et Biophysica Acta (BBA) - General Subjects, 2009
- Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancerCancer Letters, 2009
- The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cellsin vitroandin vivowith particular efficacy for small cell lung cancerMolecular Cancer Therapeutics, 2009
- The emerging role of nuclear architecture in DNA repair and genome maintenanceNature Reviews Molecular Cell Biology, 2009
- Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific functionThe Journal of cell biology, 2009
- gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatinNucleic Acids Research, 2008
- Postradiation Sensitization of the Histone Deacetylase Inhibitor Valproic AcidClinical Cancer Research, 2008
- The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and menNature Reviews Molecular Cell Biology, 2008
- Cell shape regulates global histone acetylation in human mammary epithelial cellsExperimental Cell Research, 2007
- Chromatin Modifications and Their FunctionCell, 2007