title: TGF-β regulates DNA methyltransferase expression in prostate cancer, correlates with aggressive capabilities, and predicts disease recurrence.
abstract: BACKGROUND
  DNA 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.
  
  
  RESULTS
  We 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
  Our 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.
authors: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America. q-zhang2@northwestern.edu
authors: Qiang
authors: Q
authors: Zhang
authors: Lin
authors: L
authors: Chen
authors: Brian T
authors: BT
authors: Helfand
authors: Thomas L
authors: TL
authors: Jang
authors: Vidit
authors: V
authors: Sharma
authors: James
authors: J
authors: Kozlowski
authors: Timothy Michael
authors: TM
authors: Kuzel
authors: Lihua J
authors: LJ
authors: Zhu
authors: Ximing J
authors: XJ
authors: Yang
authors: Borko
authors: B
authors: Javonovic
authors: Yinglu
authors: Y
authors: Guo
authors: Scott
authors: S
authors: Lonning
authors: Jay
authors: J
authors: Harper
authors: Beverly A
authors: BA
authors: Teicher
authors: Charles
authors: C
authors: Brendler
authors: Nengwang
authors: N
authors: Yu
authors: William J
authors: WJ
authors: Catalona
authors: Chung
authors: C
authors: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology* / Q000601:surgery; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004248:DNA (Cytosine-5-)-Methyltransferases