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CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer

Hong Zhao1, Hiroaki Shiina, Kirsten L Greene

  • 1Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California 94121, USA.

Cancer
|May 17, 2005
PubMed
Abstract

Insights

CpG methylation of the TGF-beta type 2 receptor promoter causes its loss in prostate cancer. Demethylating agents can restore TGF-beta signaling, offering a potential therapeutic strategy for this cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Transforming growth factor beta (TGF-beta) signaling is crucial and mediated by type 1 (TbetaRI) and type 2 (TbetaRII) receptors.
  • Prostate cancer often exhibits resistance to TGF-beta signaling due to diminished TbetaRII expression.

Purpose of the Study:

  • To investigate the hypothesis that CpG methylation at the TbetaRII promoter's Sp1 binding site (-140) drives TbetaRII loss in prostate cancer.
  • To explore the potential of demethylating agents in restoring TbetaRII expression.

Main Methods:

  • Analysis of TbetaRII mRNA and protein expression in 67 prostate cancer (PC) and 8 benign prostatic hyperplasia (BPH) samples.
  • Assessment of TbetaRII promoter methylation at CpG site -140 using methylation-specific PCR and bisulfite DNA sequencing.
  • Treatment of prostate cancer cell lines with 5-aza-2'-deoxycytidine to evaluate TbetaRII gene expression restoration.

Main Results:

  • TbetaRII mRNA and protein levels were significantly lower in PC samples compared to BPH.
  • CpG methylation at site -140 was more prevalent in PC than BPH and inversely correlated with TbetaRII mRNA expression.
  • Treatment with 5-aza-2'-deoxycytidine increased TbetaRII mRNA expression in PC cell lines.

Conclusions:

  • CpG methylation at the TbetaRII promoter's -140 site leads to functional loss of the TbetaRII gene in prostate cancer.
  • Demethylation therapy can potentially restore TbetaRII gene expression.
  • This study establishes the first link between prostate cancer, TGF-beta pathway loss, and TbetaRII DNA promoter methylation.

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