Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation

Mol Cancer. 2011 Oct 14;10:129. doi: 10.1186/1476-4598-10-129.

Abstract

Background: We have previously reported significant downregulation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in prostate cancer (PCa) compared to the surrounding benign tissue. UCHL1 plays an important role in ubiquitin system and different cellular processes such as cell proliferation and differentiation. We now show that the underlying mechanism of UCHL1 downregulation in PCa is linked to its promoter hypermethylation. Furthermore, we present evidences that UCHL1 expression can affect the behavior of prostate cancer cells in different ways.

Results: Methylation specific PCR analysis results showed a highly methylated promoter region for UCHL1 in 90% (18/20) of tumor tissue compared to 15% (3/20) of normal tissues from PCa patients. Pyrosequencing results confirmed a mean methylation of 41.4% in PCa whereas only 8.6% in normal tissues. To conduct functional analysis of UCHL1 in PCa, UCHL1 is overexpressed in LNCaP cells whose UCHL1 expression is normally suppressed by promoter methylation and found that UCHL1 has the ability to decrease the rate of cell proliferation and suppresses anchorage-independent growth of these cells. In further analysis, we found evidence that exogenous expression of UCHL1 suppress LNCaP cells growth probably via p53-mediated inhibition of Akt/PKB phosphorylation and also via accumulation of p27kip1 a cyclin dependant kinase inhibitor of cell cycle regulating proteins. Notably, we also observed that exogenous expression of UCHL1 induced a senescent phenotype that was detected by using the SA-ß-gal assay and might be due to increased p14ARF, p53, p27kip1 and decreased MDM2.

Conclusion: From these results, we propose that UCHL1 downregulation via promoter hypermethylation plays an important role in various molecular aspects of PCa biology, such as morphological diversification and regulation of proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence
  • Cyclin A / genetics
  • Cyclin A / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • DNA Methylation*
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Humans
  • Male
  • Phosphorylation
  • Promoter Regions, Genetic*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sequence Analysis, DNA
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination

Substances

  • CDKN1B protein, human
  • Cell Cycle Proteins
  • Cyclin A
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • UCHL1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p27
  • Proto-Oncogene Proteins c-akt
  • Ubiquitin Thiolesterase