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

Abstract

BackgroundWe 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.ResultsMethylation 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.ConclusionFrom 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.

The importance of regulatory ubiquitination in cancer and metastasis

“…Overexpression of UCHL1 in MB231 breast cells significantly decreases proliferation due to G0/G1 cell cycle arrest and apoptosis 85 . Similarly, this DUB is downregulated in some prostate cancer samples and in LNCaP cell line, and overexpression of UCHL1 suppresses the proliferation and anchorage-independent growth of LNCaP cells 86 . Further research will be required to unravel the contradicting role of UCH-L1 in different cancers.…”

Proteomic analysis of β-asarone induced cytotoxicity in human glioblastoma U251 cells

“…Recently, UCHL1 is reported to promote metastases as a deubiquitinating enzyme for HIF-1␣ [21]. On the other hand, promoter hypermethylation leading to silencing of UCHL1 has been reported in progression of prostate cancer [22], breast cancer [23], nasopharyngeal carcinoma [24], hepatocellular carcinoma and other digestive tumors [25]. In ovarian cancer cells, UCHL1 is also reported to be a tumor suppressor and knockdown of UCHL1 contributes to cisplatin resistance [26].…”

Lipoprotein lipase deficiency leads to α-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction

“…t LPL deficiency gives rise to translocation of DNMT1 from cytoplasm to nuclear, and then raises UCHL1 promoter DNA methylation level (Sasaki and Matsui, 2008;Svedruzic, 2011). u UCHL1 transcription is inhibited because of DNA hypermethylation of its promoter (Ummanni et al, 2011;Mitsui et al, 2012;Trifa et al, 2013). v UCHL1 protein decreases.…”