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 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.
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Marte
M
Jonsson
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.
Harald Bull
HB
Ragnum
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.
Cathinka Halle
CH
Julin
Department of Pathology and Molecular Genetics HUAV, University of Lleida, Lleida, Spain.
Andree
A
Yeramian
Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Trevor
T
Clancy
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.
Kari-Anne Myrum
KM
Frikstad
Department of Radiology and Nuclear Medicine, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Therese
T
Seierstad
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.
Trond
T
Stokke
Department of Pathology and Molecular Genetics HUAV, University of Lleida, Lleida, Spain.
Xavier
X
Matias-Guiu
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
Anne Hansen
AH
Ree
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Kjersti
K
Flatmark
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, 0424 Oslo, Norway.
Heidi
H
Lyng
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002843:Chromatin / Q000648:ultrastructure; D004260:DNA Repair / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D000077337:Vorinostat
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002843:Chromatin; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat