The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.
The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.
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泛素肽酶 UCHL1 通过稳定 p53 诱导 G0/G1 细胞周期停滞和凋亡，并且在乳腺癌中经常沉默
DOI：
10.1371/journal.pone.0029783
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tao Q
中科院分区：
文献类型：
--
作者：
Xiang T;Li L;Yin X;Yuan C;Tan C;Su X;Xiong L;Putti TC;Oberst M;Kelly K;Ren G;Tao Q
背景乳腺癌(BRCA)是一种由基因突变和环境因素共同作用的复杂疾病。近年来的研究表明，表观基因调控异常在其发病机制中也起着重要作用。泛素羧基末端酯酶L1(UCHL1)是一种肿瘤抑制基因，在多种肿瘤中被启动子甲基化抑制，但其在乳腺肿瘤发生中的作用和变化尚不清楚。方法/主要发现我们发现UCHL1在乳腺癌细胞系和肿瘤组织中经常下调或沉默，但在正常乳腺组织和乳腺上皮细胞中很容易表达。UCHL1基因启动子甲基化在10个乳腺癌细胞系中有9个(90%)和在66个原发肿瘤中有53个(80%)检测到，而在正常乳腺组织中很少检测到，这与临床分期和孕激素受体状态密切相关。药物去甲基化重新激活了UCHL1的表达，同时伴随着启动子去甲基化。异位表达UCHL1通过诱导G0/G1期细胞周期停滞和细胞凋亡，显著抑制乳腺肿瘤细胞集落形成和增殖。亚细胞定位研究表明，UCHL1增加了P53的胞浆丰度。我们进一步发现，UCHL1诱导P53积聚，降低MDM2蛋白水平，随后上调p21的表达，以及caspase3和PARP的切割，但在催化突变UCHL1C9os表达的细胞中没有。结论/意义UCHL1在乳腺肿瘤发生过程中通过诱导G0/G1期细胞周期停滞和细胞凋亡来发挥其抑瘤作用，这需要其脱泛素酶活性。启动子CpG甲基化使其频繁沉默，可能成为乳腺癌的潜在肿瘤标志物。
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.
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DOI：
10.1158/1055-9965.epi-08-0192
发表时间：
2008-10
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Brait M;Begum S;Carvalho AL;Dasgupta S;Vettore AL;Czerniak B;Caballero OL;Westra WH;Sidransky D;Hoque MO
通讯作者：
Hoque MO
影响因子：
11.2
作者：
Cheng, Yingduan;Geng, Hua;Tao, Qian
通讯作者：
Tao, Qian
影响因子：
6.4
作者：
Okochi-Takada, Eriko;Nakazawa, Kazuyuki;Ushijima, Toshikazu
通讯作者：
Ushijima, Toshikazu
影响因子：
3.7
作者：
Cui Y;Ying Y;van Hasselt A;Ng KM;Yu J;Zhang Q;Jin J;Liu D;Rhim JS;Rha SY;Loyo M;Chan AT;Srivastava G;Tsao GS;Sellar GC;Sung JJ;Sidransky D;Tao Q
通讯作者：
Tao Q
影响因子：
64.5
作者：
Liu, YC;Fallon, L;Lansbury, PT
通讯作者：
Lansbury, PT