Human Molecular Genetics Advance Access originally published online on July 7, 2009
Human Molecular Genetics 2009 18(19):3594-3604; doi:10.1093/hmg/ddp307
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Generation of an epigenetic signature by chronic hypoxia in prostate cells
1 The UCD School of Medicine and Medical Science and The UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland, 2 Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK, 3 Centre for Colorectal Disease, Education and Research Centre, St Vincents University Hospital (SVUH), Elm Park, Dublin 4, Ireland and 4 National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
* To whom correspondence should be addressed. Tel: +353 17166742; Fax: +353 17166888; Email: jennywatson2008{at}gmail.com
Received May 21, 2009; Accepted July 1, 2009
Increasing levels of tissue hypoxia have been reported as a natural feature of the aging prostate gland and may be a risk factor for the development of prostate cancer. In this study, we have used PwR-1E benign prostate epithelial cells and an equivalently aged hypoxia-adapted PwR-1E sub-line to identify phenotypic and epigenetic consequences of chronic hypoxia in prostate cells. We have identified a significantly altered cellular phenotype in response to chronic hypoxia as characterized by increased receptor-mediated apoptotic resistance, the induction of cellular senescence, increased invasion and the increased secretion of IL-1β, IL6, IL8 and TNF
cytokines. In association with these phenotypic changes and the absence of HIF-1 protein expression, we have demonstrated significant increases in global levels of DNA methylation and H3K9 histone acetylation in these cells, concomitant with the increased expression of DNA methyltransferase DMNT3b and gene-specific changes in DNA methylation at key imprinting loci. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic hypoxic conditions in the prostate. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular phenotype with a potential role in tumour development.