PURPOSE: Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis. EXPERIMENTAL DESIGN: UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells. RESULTS: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14(ARF)/Mdm2 p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14(ARF) protein half-life and shortened MDM2 protein half-life. CONCLUSIONS: These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor. Copyright 2010 AACR.
PURPOSE:Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis. EXPERIMENTAL DESIGN:UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells. RESULTS: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14(ARF)/Mdm2p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14(ARF) protein half-life and shortened MDM2 protein half-life. CONCLUSIONS: These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor. Copyright 2010 AACR.
Authors: David A Kleiman; Toni Beninato; Samuel Sultan; Michael J P Crowley; Brendan Finnerty; Ritu Kumar; Nicole C Panarelli; Yi-Fang Liu; Michael D Lieberman; Marco Seandel; Todd Evans; Olivier Elemento; Rasa Zarnegar; Thomas J Fahey Journal: Ann Surg Oncol Date: 2014-05-23 Impact factor: 5.344
Authors: Sumegha Mitra; Saad Sammani; Ting Wang; David L Boone; Nuala J Meyer; Steven M Dudek; Liliana Moreno-Vinasco; Joe G N Garcia; Jeffrey R Jacobson Journal: Am J Respir Crit Care Med Date: 2011-11-01 Impact factor: 21.405
Authors: E Ayroldi; M G Petrillo; A Bastianelli; M C Marchetti; S Ronchetti; G Nocentini; L Ricciotti; L Cannarile; C Riccardi Journal: Cell Death Differ Date: 2014-08-29 Impact factor: 15.828