E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation
E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation
复制标题
E3 泛素连接酶 RNF126 通过靶向肿瘤抑制因子 p21 进行泛素介导的降解来促进癌细胞增殖
DOI：
10.1158/0008-5472.can-12-0562
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发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
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作者：
Zhi, Xu;Zhao, Dong;Chen, Ceshi
为了鉴定作为抗癌靶点的新型致癌E3泛素连接酶，我们在MDA-MB-231乳腺癌细胞系和PC 3前列腺癌细胞系中使用磺基罗丹明B测定筛选了含有针对555个个体E3的siRNA池的E3泛素连接酶siRNA文库。RNF 126被鉴定并验证为来自该筛选的候选物。RNF 126的敲低显著降低了这些癌细胞系中的细胞活力。一致地，RNF 126敲低延迟细胞周期G（1）-S进程并降低细胞增殖。使用蛋白质阵列分析，我们发现RNF 126沉默增加了MDA-MB-231和PC 3中的细胞周期依赖性激酶抑制剂p21（cip）蛋白水平。RNF 126的敲低稳定了p21蛋白，而不是增加了p21 mRNA水平。我们发现RNF 126与p21相互作用，并且RNF 126过表达以E3连接酶活性依赖的方式增加p21蛋白泛素化。RNF 126敲低诱导的MDA-MB-231和PC-3中细胞活力的丧失可以通过p21的耗尽而部分挽救。PC 3中RNF 126的稳定敲低抑制了SCID小鼠的肿瘤生长。最后，我们发现RNF 126在乳腺癌细胞系中高度表达，并与p21表达水平呈负相关。这些发现表明RNF 126通过靶向p21进行泛素介导的降解来促进癌细胞增殖。RNF 126可能是乳腺癌和前列腺癌的新治疗靶点。Cancer Res; 73（1）; 385-94.（C）2012年AACR。
To identify novel oncogenic E3 ubiquitin ligases as anticancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the sulphorhodamine B assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell-cycle G(1)-S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell-cycle dependent kinase inhibitor p21(cip) protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. Cancer Res; 73(1); 385-94. (C)2012 AACR.