UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer.
UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer.
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DOI：
10.7150/ijbs.72629
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发表时间：
2022
影响因子：
9.2
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Peng, Shengmeng;Chen, Xu;Huang, Chaoyun;Yang, Chenwei;Situ, Minyi;Zhou, Qianghua;Ling, Yihong;Huang, Hao;Huang, Ming;Zhang, Yangjie;Cheng, Liang;Zhang, Qiang;Guo, Zhenghui;Lai, Yiming;Huang, Jian
骨转移是前列腺癌(Pca)的主要转移部位，也是导致死亡人数最多的肿瘤。骨转移的机制复杂，尚未完全阐明。通过测序和分析PCa骨转移的关键途径，我们发现Pca骨转移过程中的一个重要特征是p16INK4a(P16)低蛋白水平引起的G1/S转换加速。有趣的是，我们证明了UBE2S通过K11结合并降解p16，而不是K48或K63连接的泛素化，这在体内和体外都加速了PCa肿瘤细胞G1/S的转变。此外，UBE2S还通过K11连接的泛素化来稳定β-连环蛋白，导致PCa骨转移中肿瘤细胞的迁移和侵袭增强。根据我们的队列和公共数据库，UBE2S在骨转移中过表达，并与PCa的高Gleason评分、晚期淋巴结转移和不良预后呈正相关。最后，头孢甘氨酸靶向UBE2S在体外抑制了Pca的增殖和侵袭，并在体内抑制了Pca的骨转移。本研究创新性地发现，UBE2S通过降解p16和通过K11连接的泛素化稳定β-连环蛋白，在前列腺癌的骨转移中发挥致癌作用，提示它可能成为转移性前列腺癌治疗的多潜能靶点。
Bone metastasis is the main site of metastasis and causes the most deaths in patients with prostate cancer (PCa). The mechanism of bone metastasis is complex and not fully clarified. By RNA sequencing and analysing key pathways in bone metastases of PCa, we found that one of the most important characteristics during PCa bone metastasis was G1/S transition acceleration caused by low protein levels of p16INK4a (p16). Interestingly, we demonstrated that UBE2S bound and degraded p16 through K11- rather than K48- or K63-linked ubiquitination, which accelerated PCa tumour cell G1/S transition in vivo and in vitro. Moreover, UBE2S also stabilized β-catenin through K11-linked ubiquitination, leading to enhanced migration and invasion of tumour cells in PCa bone metastasis. Based on our cohorts and public databases, UBE2S was overexpressed in bone metastases and positively correlated with a high Gleason score, advanced nodal metastasis status and poor prognosis in PCa. Finally, targeting UBE2S with cephalomannine inhibited proliferation and invasion in vitro, and bone metastasis of PCa in vivo. This study innovatively discovered that UBE2S plays an oncogenic role in bone metastasis of PCa by degrading p16 and stabilizing β-catenin via K11-linked ubiquitination, suggesting that it may serve as a multipotent target for metastatic PCa treatment.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
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11.5
作者：
Iglesias-Gato, Diego;Thysell, Elin;Wikstrom, Pernilla
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Wikstrom, Pernilla
影响因子：
45.3
作者：
Chakravarti, Arnab;DeSilvio, Michelle;Shipley, William
通讯作者：
Shipley, William
影响因子：
5.1
作者：
Ameri, A.;Alidoosti, A.;Fadavi, P.
通讯作者：
Fadavi, P.
影响因子：
9.2
作者：
Li，Tonghui;Wang，Fangfang;Lu，Shan
通讯作者：
Lu，Shan