DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation.
Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
D
D
Pellacani
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
D
D
Kestoras
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
A P
AP
Droop
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
F M
FM
Frame
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
P A
PA
Berry
Prostate Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
M G
MG
Lawrence
York District Hospital, Wigginton Road, City Centre, York, UK.
M J
MJ
Stower
1] Castle Hill Hospital, Castle Rd, Cottingham, East Yorkshire, UK [2] Hull York Medical School, University of Hull, Hull, UK.
M S
MS
Simms
1] Castle Hill Hospital, Castle Rd, Cottingham, East Yorkshire, UK [2] Hull York Medical School, University of Hull, Hull, UK.
V M
VM
Mann
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
A T
AT
Collins
Prostate Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
G P
GP
Risbridger
YCR Cancer Research Unit, Department of Biology, University of York, Wentworth Way, York, UK.
N J
NJ
Maitland
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014407:Tumor Cells, Cultured