Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition

Histone deacetylase inhibitors (HDACis) like vorinostat are promising radiosensitisers in prostate cancer, but their effect under hypoxia is not known. We investigated gene expression associated with radiosensitisation of normoxic and hypoxic prostate cancer cells by vorinostat. Cells were exposed t...

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Bibliographic Details
Published in:British journal of cancer 2016-10, Vol.115 (8), p.929-939
Main Authors: Jonsson, Marte, Ragnum, Harald Bull, Julin, Cathinka Halle, Yeramian, Andree, Clancy, Trevor, Frikstad, Kari-Anne Myrum, Seierstad, Therese, Stokke, Trond, Matias-Guiu, Xavier, Ree, Anne Hansen, Flatmark, Kjersti, Lyng, Heidi
Format: Article
Language:English
Subjects:
Adenocarcinoma - enzymology
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Antineoplastic Agents - pharmacology
Biomarkers
Biomarkers, Tumor
Cell cycle
Cell Cycle - drug effects
Cell Hypoxia
Cell Line, Tumor
Chromatin - ultrastructure
DNA repair
DNA Repair - genetics
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene Knockdown Techniques
Genes, p53
Genomics
Histone Deacetylase Inhibitors - pharmacology
Humans
Hydroxamic Acids - pharmacology
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Male
Medical research
Mutation
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Prostate cancer
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Proteins
Radiation therapy
Radiation Tolerance - drug effects
Radiation Tolerance - genetics
Radiation-Sensitizing Agents - pharmacology
RNA Interference
Survival analysis
Transcriptome - drug effects
Translational Therapeutics
Tumor Stem Cell Assay
Tumor Suppressor Protein p53 - antagonists & inhibitors
Tumors
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Summary:Histone deacetylase inhibitors (HDACis) like vorinostat are promising radiosensitisers in prostate cancer, but their effect under hypoxia is not known. We investigated gene expression associated with radiosensitisation of normoxic and hypoxic prostate cancer cells by vorinostat. Cells were exposed to vorinostat under normoxia or hypoxia and subjected to gene expression profiling before irradiation and clonogenic survival analysis. Pretreatment with vorinostat led to radiosensitisation of the intrinsically radioresistant DU 145 cells, but not the radiosensitive PC-3 and 22Rv1 cells, and was independent of hypoxia status. Knockdown experiments showed that the sensitisation was not caused by repression of hypoxia-inducible factor HIF1 or tumour protein TP53. Global deregulation of DNA repair and chromatin organisation genes was associated with radiosensitisation under both normoxia and hypoxia. A radiosensitisation signature with expression changes of 56 genes was generated and valid for both conditions. For eight signature genes, baseline expression also correlated with sensitisation, showing potential as pretreatment biomarker. The hypoxia independence of the signature was confirmed in a clinical data set. Pretreatment with HDACi may overcome radioresistance of hypoxic prostate tumours by similar mechanisms as under normoxia. We propose a gene signature to predict radiosensitising effects independent of hypoxia status.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2016.278