Generation of an epigenetic signature by chronic hypoxia in prostate cells.
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-1 beta, IL6, IL8 and TNFalpha cytokines. In association with these phenotypic changes and the absence of HIF-1 alpha 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.
Watson
Jenny A
JA
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. jennywatson2008@gmail.com
Watson
Chris J
CJ
McCrohan
Ann-Maria
AM
Woodfine
Kathryn
K
Tosetto
Miriam
M
McDaid
Jennifer
J
Gallagher
Emma
E
Betts
David
D
Baugh
John
J
O'Sullivan
Jacintha
J
Murrell
Adele
A
Watson
R William G
RW
McCann
Amanda
A
D000107:Acetylation; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism
C000717967:DNMT3A protein, human; D006657:Histones; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A