The tumor suppressor UCHL1 forms a complex with p53/MDM2/ARF to promote p53 signaling and is frequently silenced in nasopharyngeal carcinoma.
OBJECTIVE
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.


METHODS
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.
Li
Lili
L
State Key Laboratory in Oncology in South China/Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, Hong Kong.
Tao
Qian
Q
Jin
Hongchuan
H
van Hasselt
Andrew
A
Poon
Fan Fong
FF
Wang
Xian
X
Zeng
Mu-Sheng
MS
Jia
Wei-Hua
WH
Zeng
Yi-Xin
YX
Chan
Anthony T C
AT
Cao
Ya
Y
D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
D010446:Peptide Fragments; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C482860:UCHL1 protein, human; D025801:Ubiquitin; C489230:ubiquitin 50-59, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D043222:Ubiquitin Thiolesterase