USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells.
USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells.
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DOI：
10.1186/s13046-021-02008-3
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发表时间：
2021-06-21
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Liao Y;Shao Z;Liu Y;Xia X;Deng Y;Yu C;Sun W;Kong W;He X;Liu F;Guo Z;Chen G;Tang D;Gan H;Liu J;Huang H
肝细胞癌（HCC）由于其高度的增殖和转移性，仍然是医学上的一个挑战。虽然去泛素化酶（DUBs）在调节蛋白质降解中起关键作用，但其在HCC中的病理作用尚未完全阐明。通过生物量光谱法、免疫共沉淀法、免疫印迹法和免疫荧光法，我们确定核糖体蛋白S16（RPS 16）是泛素特异性肽酶1（USP 1）的关键底物。在细胞培养物、异种移植小鼠模型和临床观察中评价了USP 1-RPS 16轴在HCC进展中的作用。我们发现USP 1与RPS 16相互作用。USP 1的缺失增加了K48连接的泛素化RPS 16的水平，导致蛋白酶体依赖性RPS 16降解。相反，USP 1-WT而不是USP 1-C90 A（DUB失活突变体）的过表达降低了K48连接的泛素化RPS 16的水平，从而稳定了RPS 16。因此，USP 1耗竭模拟RPS 16缺陷对生长和转移的抑制，而RPS 16的转染增强再表达恢复了USP 1缺陷型HCC细胞中的致癌样活性。重要的是，肝组织中USP 1和RPS 16的高表达是HCC患者生存不良的预后因素。这些发现揭示了USP 1-RPS 16通路激活在驱动HCC中的先前未被认识的作用，这可能进一步发展为癌症治疗的新策略。在线版本包含补充材料，可通过10.1186/s13046-021-02008-3获得。
Hepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated. By using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations. We show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients. These findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment. The online version contains supplementary material available at 10.1186/s13046-021-02008-3.
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影响因子：
15.9
作者：
Lee, Jin-Ku;Chang, Nakho;Lee, Jeongwu
通讯作者：
Lee, Jeongwu
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
HCC 血管侵袭的基因组分析揭示了分子驱动因素和预测生物标志物。
DOI：
10.1002/hep.31614
发表时间：
2021-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Krishnan MS;Rajan Kd A;Park J;Arjunan V;Garcia Marques FJ;Bermudez A;Girvan OA;Hoang NS;Yin J;Nguyen MH;Kothary N;Pitteri S;Felsher DW;Dhanasekaran R
通讯作者：
Dhanasekaran R
影响因子：
7.7
作者：
Fang Z;Cao B;Liao JM;Deng J;Plummer KD;Liao P;Liu T;Zhang W;Zhang K;Li L;Margolin D;Zeng SX;Xiong J;Lu H
通讯作者：
Lu H
DOI：
10.1158/1078-0432.ccr-16-2692
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Das DS;Das A;Ray A;Song Y;Samur MK;Munshi NC;Chauhan D;Anderson KC
通讯作者：
Anderson KC