The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis in urothelial bladder cancer.
The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis in urothelial bladder cancer.
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APC/C E3 连接酶亚基 ANAPC11 介导 FOXO3 蛋白降解，促进膀胱尿路上皮癌的细胞增殖和淋巴结转移。
DOI：
10.1038/s41419-023-06000-x
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发表时间：
2023-08-12
影响因子：
9
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Yan, Dong;He, Qingqing;Pei, Lu;Yang, Meihua;Huang, Lifang;Kong, Jianqiu;He, Wang;Liu, Hao;Xu, Shizhong;Qin, Haide;Lin, Tianxin;Huang, Jian
膀胱尿路上皮癌（UBC）是世界上最常见的恶性肿瘤之一，具有显著的肿瘤异质性。阐明可用于治疗侵袭性UBC的分子机制是一个特别相关的目标。蛋白质泛素化是一种重要的翻译后修饰，通过蛋白酶体介导靶蛋白的降解。然而，异常蛋白泛素化在UBC发展中的作用及其驱动肿瘤进展的潜在机制仍不清楚。在这项研究中，利用成簇规则间隔短回文重复序列（CRISPR）-CRISPR相关蛋白（Cas）9技术，我们确定了泛素E3连接酶ANAPC 11，后期促进复合物/环体（APC/C）的关键亚基，作为UBC细胞中的潜在致癌分子。我们的临床分析表明，ANAPC 11的高表达与UBC患者的高T分期、阳性淋巴结（LN）转移和不良预后显著相关。通过一系列的体外实验，我们证明ANAPC 11能增强UBC细胞的增殖和侵袭能力，而敲除ANAPC 11则能抑制UBC细胞在体内的生长和LN转移。通过进行免疫沉淀结合质谱分析，我们证实ANAPC 11增加了叉头转录因子FOXO 3的泛素化水平。FOXO 3蛋白稳定性的降低导致细胞周期调节因子p21的下调和GULP 1（雄激素受体信号传导的下游效应子）表达的降低。总之，这些发现表明ANAPC 11通过调节FOXO 3蛋白降解在UBC中发挥致癌作用。ANAPC 11-FOXO 3调节轴可能成为UBC的新治疗靶点。
Urothelial bladder cancer (UBC) is one of the most prevalent malignancies worldwide, with striking tumor heterogeneity. Elucidating the molecular mechanisms that can be exploited for the treatment of aggressive UBC is a particularly relevant goal. Protein ubiquitination is a critical post-translational modification (PTM) that mediates the degradation of target protein via the proteasome. However, the roles of aberrant protein ubiquitination in UBC development and the underlying mechanisms by which it drives tumor progression remain unclear. In this study, taking advantage of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 technology, we identified the ubiquitin E3 ligase ANAPC11, a critical subunit of the anaphase-promoting complex/cyclosome (APC/C), as a potential oncogenic molecule in UBC cells. Our clinical analysis showed that elevated expression of ANAPC11 was significantly correlated with high T stage, positive lymph node (LN) metastasis, and poor outcomes in UBC patients. By employing a series of in vitro experiments, we demonstrated that ANAPC11 enhanced the proliferation and invasiveness of UBC cells, while knockout of ANAPC11 inhibited the growth and LN metastasis of UBC cells in vivo. By conducting immunoprecipitation coupled with mass spectrometry, we confirmed that ANAPC11 increased the ubiquitination level of the Forkhead transcription factor FOXO3. The resulting decrease in FOXO3 protein stability led to the downregulation of the cell cycle regulator p21 and decreased expression of GULP1, a downstream effector of androgen receptor signaling. Taken together, these findings indicated that ANAPC11 plays an oncogenic role in UBC by modulating FOXO3 protein degradation. The ANAPC11–FOXO3 regulatory axis might serve as a novel therapeutic target for UBC.
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影响因子：
46.9
作者：
Evers, Bastiaan;Jastrzebski, Katarzyna;Bernards, Rene
通讯作者：
Bernards, Rene
影响因子：
64.8
作者：
Chang L;Zhang Z;Yang J;McLaughlin SH;Barford D
通讯作者：
Barford D
DOI：
10.1073/pnas.2118285119
发表时间：
2022-03-15
影响因子：
11.1
作者：
Guo X;Li Z;Zhu X;Zhan M;Wu C;Ding X;Peng K;Li W;Ma X;Lv Z;Lu L;Xue L
通讯作者：
Xue L
影响因子：
16.6
作者：
Gill MK;Christova T;Zhang YY;Gregorieff A;Zhang L;Narimatsu M;Song S;Xiong S;Couzens AL;Tong J;Krieger JR;Moran MF;Zlotta AR;van der Kwast TH;Gingras AC;Sicheri F;Wrana JL;Attisano L
通讯作者：
Attisano L
影响因子：
--
作者：
Brown AK;Webb AE
通讯作者：
Webb AE