Journal
CANCER
Volume 104, Issue 1, Pages 44-52Publisher
WILEY
DOI: 10.1002/cncr.21135
Keywords
T beta RII; CpG methylation; human; prostate cancer
Categories
Funding
- NCI NIH HHS [R01CA1018447] Funding Source: Medline
- NIA NIH HHS [R01AG21418] Funding Source: Medline
- NIDDK NIH HHS [T32DK07790] Funding Source: Medline
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BACKGROUND. The action of transforming growth factor beta (TGF-beta) is mediated through type 1 (T beta RI) and type 2 (T beta RII) receptors. Prostate cancer cells are often resistant to TGF-beta signaling due to loss of T beta RII expression. The authors of the current study hypothesized that CpG methylation of the T beta RII promoter at the Sp1 binding site - 140 mediates this loss of T beta RII expression in prostate cancer. METHODS. Sixty-seven prostate cancer (PC) samples, 8 benign prostatic hyperplasia (BPH) samples, and 4 prostate cancer cell lines (DUPro, LNCaP, ND-1 and PC-3) were analyzed for 1) T beta R11 mRNA expression by semiquantitative RT-PCR, 2) T beta R11 protein expression by immunohistochemistry, and 3) T beta RII promoter methylation at CpG site - 140 by methylation specific PCR and bisulfite DNA sequencing. Prostate cancer cell lines were treated with the demethylating agent 5aza2' deoxycytidine to determine if T beta RII gene expression could be increased by blocking promoter methylation. RESULTS. mRNA and protein expression of T beta RII was lower in the PC samples than in the BPH samples. CpG methylation at site - 140 was higher in PC than in BPH (P < 0.01). Promoter methylation was inversely correlated with T beta R11 mRNA expression in the PC and BPH samples (P < 0.0001). PC3, NDI, and DUPro T beta RII mRNA expression increased following treatment of cells with 5-aza-2'-deoxycytidine. CONCLUSION. CpG methylation of the T beta RII promoter at CPG site -140 leads to functional loss of the T beta RII gene in prostate cancer. Treatment with 5-aza-2' deoxycytidine can restore gene expression. The current study results report the first association between prostate cancer and loss of the TGF-beta signaling pathway by T beta RII DNA promoter methylation.
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