The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer
Autor: | Kathleen Kelly, Chenfu Yuan, Qian Tao, Thomas C. Putti, Cui Tan, Michael Oberst, Lei Xiong, Guosheng Ren, Lili Li, Xuedong Yin, Xianwei Su, Tingxiu Xiang |
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Jazyk: | angličtina |
Rok vydání: | 2012 |
Předmět: |
Male
lcsh:Medicine Apoptosis medicine.disease_cause Molecular Cell Biology Promoter Regions Genetic lcsh:Science Regulation of gene expression Multidisciplinary Reverse Transcriptase Polymerase Chain Reaction Obstetrics and Gynecology Cell cycle Gene Expression Regulation Neoplastic Oncology DNA methylation Medicine Epigenetics Female Ubiquitin Thiolesterase Research Article Adult Blotting Western Breast Neoplasms Biology Resting Phase Cell Cycle Cell Line Molecular Genetics Breast cancer Cell Line Tumor Genetics Biomarkers Tumor medicine Humans Tumor marker Gene Expression Profiling lcsh:R G1 Phase Cancers and Neoplasms Cell Cycle Checkpoints DNA Methylation medicine.disease Molecular biology Cancer research CpG Islands Ectopic expression lcsh:Q Tumor Suppressor Protein p53 Carcinogenesis |
Zdroj: | PLoS ONE, Vol 7, Iss 1, p e29783 (2012) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | Background Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear. Methodology/Principal Findings We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells. Conclusions/Significance UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer. |
Databáze: | OpenAIRE |
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