Open Access Research

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

Ramesh Ummanni1, Edgar Jost2, Melanie Braig1, Frithjof Lohmann3, Frederike Mundt1, Christine Barett1, Thorsten Schlomm4, Guido Sauter5, Tina Senff2, Carsten Bokemeyer1, Holger Sültmann6, Catherine Meyer-Schwesinger3, Tim H Brümmendorf12 and Stefan Balabanov1*

Author Affiliations

1 Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumour Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany

2 Klinik für Onkologie, Hämatologie und Stammzelltransplantation, RWTH Aachen University, Aachen, Germany

3 Department of Internal Medicine, Nephrology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany

4 Martini-Clinic, Prostate Cancer Center, University Hospital Eppendorf (UKE), Hamburg, Germany

5 Department of Pathology, University Hospital Eppendorf (UKE), Hamburg, Germany

6 Cancer Genome Research, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

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Molecular Cancer 2011, 10:129  doi:10.1186/1476-4598-10-129

Published: 14 October 2011

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:
prostate cancer; UCHL1; ubiquitin system; tumour suppression; signalling