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

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.

SUBMITTER: Ummanni R

PROVIDER: S-EPMC3212821 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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

Ummanni Ramesh R Jost Edgar E Braig Melanie M Lohmann Frithjof F Mundt Frederike F Barett Christine C Schlomm Thorsten T Sauter Guido G Senff Tina T Bokemeyer Carsten C Sültmann Holger H Meyer-Schwesinger Catherine C Brümmendorf Tim H TH Balabanov Stefan S

Molecular cancer 20111014

<h4>Background</h4>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 ...[more]

PMID: 21999842

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Project description:BACKGROUND:The ubiquitin-proteasome system regulate p53, caspase and Bcl-2 family proteins, and is crucial for the degradation of the defective germ cells in testes. Purpose: to evaluate the concentration of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in the blood plasma of boys with cryptorchidism and if there is any correlation with patient age. METHODS:Patients-50 boys aged 1-4 years (median = 2,4y.) with unilateral cryptorchidism. Exclusion criteria were: previous human chorionic gonadotropin treatment, an abnormal karyotype, endocrine or immunological disorders or any long-term medication. The control group-50 healthy, age matched boys (aged 1-4 years, median = 2,1y.), admitted to the Pediatric Surgery Department for planned herniotomy. To investigate UCHL1 in blood plasma of boys with cryptorchidism, we used a novel technique Surface PLASMON RESONANCE Imaging (SPRI). RESULTS:The median concentration of UCHL1 in the blood plasma of boys with cryptorchidism, was 5-folds higher than in boys with inguinal hernia, whose testicles were located in the scrotum. We also noticed statistically significant difference between UCHL1 levels in boys with cryptorchidism up to 2 years old, and above 2 years old. Older boys, whose testicles since birth were located in the inguinal pouch or in the abdominal cavity, had higher concentration of UCHL1 in their blood plasma, than boys from younger group. In the group of cryptorchid boys, we also found slightly lower concentrations of INSL3, without statistical significance and no correlation with UCHL1 levels. CONCLUSIONS:Uchl1 concentrations in the blood plasma of boys with cryptorchidism, may reflect the heat-induced apoptosis of germ cells. Higher UCHL1 concentrations in older boys with undescended testicles, probably express intensity of germ cell apoptosis, more extensive when testicles are subjected to heat-stress for longer period. Further analyses of UCHL1 may help to elucidate its role in mechanisms influencing spermatogenesis.

Project description:Background: Renal cell carcinoma (RCC) is one of the most common malignant tumours of the urinary system. However, the aetiology and pathogenesis of RCC remain unclear. The C2H2 zinc finger protein (ZNF) family is the largest transcriptional regulatory factor family found in mammals, and Krüppel-associated box domain-containing zinc finger proteins (KRAB-ZFPs) constitute the largest subfamily of the C2H2 zinc finger protein family and play an important role in the occurrence and development of tumours. The aim of this study was to explore the role of abnormal methylation of ZNF471 in the development of renal carcinoma. Methods: In this study, we first used the TCGA and EWAS Data Hub databases to analyse the expression and methylation levels of ZNF471 in renal carcinoma tissues and adjacent normal tissues. Second, we collected samples of renal cancer and adjacent normal tissues at Peking University First Hospital to investigate the expression and methylation level of ZNF471 in renal cancer tissues and the relationships between these levels and the clinicopathological features and prognosis of patients with renal cancer. Next, we investigated the effects of ZNF471 on the proliferation, metastasis, cell cycle progression, and apoptosis of renal cell carcinoma cells by cell biology experiments. Finally, we elucidated the underlying molecular mechanisms of ZNF471 in renal cell carcinoma by transcriptome sequencing, bioinformatics analysis and molecular biology experiments. Results: The expression of ZNF471 in renal carcinoma tissues and cell lines was significantly lower than that in adjacent normal tissues and cell lines due to abnormal promoter CpG methylation. Furthermore, the expression of ZNF471 in renal carcinoma tissues was negatively correlated with tumour stage and grade in patients with renal carcinoma. The results of the cell biology experiments showed that ZNF471 could significantly inhibit the proliferation, migration and cell cycle progression of renal cell carcinoma cells and promote apoptosis in these cells. In addition, ZNF471 could interact with BANP and suppress the malignant phenotype of RCC by inactivating the PI3K/AKT/mTOR signalling pathway. Conclusions: As an important tumour suppressor, ZNF471 can interact with BANP in renal cancer cells and inhibit the activation of the PI3K/AKT/mTOR signalling pathway, thereby inhibiting the occurrence and development of renal cancer.

Dataset Information

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

Publications

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

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