Abstract
BackgroundDNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.Methodology/Principal FindingsWe used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Conclusions and SignificanceOur findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.
Highlights
TGF-b is a pleiotropic growth factor that has been implicated in multiple, and often diametrically opposed functions, including cell proliferation, cell growth arrest, differentiation, and apoptosis [1], [2]
Our findings demonstrate that CaP derived TGF-b may induce the expression of DNA methyltransferase (DNMT) in CaP which is associated with methylation of its receptors and the aggressive potential of CaP
DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy
Summary
TGF-b is a pleiotropic growth factor that has been implicated in multiple, and often diametrically opposed functions, including cell proliferation, cell growth arrest, differentiation, and apoptosis [1], [2]. It is well known that a reduction or loss of expression of TGF-b receptors (TbRs) enables cancer cells to escape the growth inhibitory effect of TGF-b and to gain a growth advantage, the cellular mechanism(s) underlying these events in human CaP cells remains undefined. We have demonstrated that the loss of TbRs expression by promoter methylation is associated with insensitivity to TGF-b-mediated growth inhibition [4]. DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-b receptors (TbRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-b in aggressive prostate cancer (CaP). We describe the mechanism of TGF-b-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy
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