Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation
Open Access
- 14 October 2011
- journal article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 10 (1), 129
- https://doi.org/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.Keywords
This publication has 43 references indexed in Scilit:
- Identification of Clinically Relevant Protein Targets in Prostate Cancer with 2D-DIGE Coupled Mass Spectrometry and Systems Biology Network PlatformPLOS ONE, 2011
- Expression and Functional Studies of Ubiquitin C-Terminal Hydrolase L1 Regulated GenesPLOS ONE, 2009
- Positive Reciprocal Regulation of Ubiquitin C-Terminal Hydrolase L1 and β-Catenin/TCF SignalingPLOS ONE, 2009
- Regulation and Cellular Roles of Ubiquitin-Specific Deubiquitinating EnzymesAnnual Review of Biochemistry, 2009
- Epigenetic regulation and molecular characterization of C/EBPα in pancreatic cancer cellsInternational Journal of Cancer, 2008
- The role of PGP9.5 as a tumor suppressor gene in human cancerInternational Journal of Cancer, 2008
- Prostate cancer epidemiologyFrontiers in Bioscience-Landmark, 2006
- Oncogene-induced senescence as an initial barrier in lymphoma developmentNature, 2005
- Interaction and colocalization of PGP9.5 with JAB1 and p27Kip1Oncogene, 2002
- Cancer statistics, 1999CA: A Cancer Journal for Clinicians, 1999