title: The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Xuedong
authors.initials: X
authors.lastname: Yin
authors.forename: Chenfu
authors.initials: C
authors.lastname: Yuan
authors.forename: Cui
authors.initials: C
authors.lastname: Tan
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Putti
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
authors.forename: Guosheng
authors.initials: G
authors.lastname: Ren
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D016193:G1 Phase; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D016192:Resting Phase, Cell Cycle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase