USP28 facilitates pancreatic cancer progression through activation of Wnt/β-catenin pathway via stabilising FOXM1.
USP28 facilitates pancreatic cancer progression through activation of Wnt/β-catenin pathway via stabilising FOXM1.
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USP28 通过稳定 FOXM1 激活 Wnt/β-catenin 通路促进胰腺癌进展
DOI：
10.1038/s41419-021-04163-z
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发表时间：
2021-09-28
影响因子：
9
通讯作者：
Peng X
中科院分区：
文献类型：
--
作者：
Chen L;Xu Z;Li Q;Feng Q;Zheng C;Du Y;Yuan R;Peng X
泛素化是一种重要的翻译后修饰，可以被称为去泛素化酶（DUBs）的酶家族逆转。泛素特异性蛋白酶28（USP 28）是DUBs家族的一员，在各种癌症中作为潜在的肿瘤促进剂发挥作用。然而，USP 28在胰腺癌（PC）中的生物学功能和临床意义尚不清楚。在这里，我们发现PC肿瘤与正常胰腺组织相比具有更高的USP 28表达，并且高USP 28水平与PC患者的恶性表型和较短的生存期显著相关。USP 28的过表达加速PC细胞生长，而USP 28敲低在体外和体内均损害PC细胞生长。此外，我们发现USP 28通过促进细胞周期进程和抑制凋亡来促进PC细胞生长。在机制上，USP 28去泛素化并稳定FOXM 1，FOXM 1是Wnt/β-连环蛋白信号传导的关键介质。USP 28介导的FOXM 1稳定显著促进了细胞核β-连环蛋白反式激活，这反过来导致Wnt/β-连环蛋白途径的激活。最后，FOXM 1表达的恢复消除了USP 28沉默的抗肿瘤作用。因此，USP 28通过增强FOXM 1介导的Wnt/β-catenin信号通路参与PC的发病机制，并可能成为PC病例的潜在诊断和治疗靶点。
Ubiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/β-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus β-catenin trans-activation, which in turn led to the activation of the Wnt/β-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/β-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.
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影响因子：
8
作者：
通讯作者：
--
FOXM1 通过 LDHA 表达的反式激活促进瓦尔堡效应和胰腺癌进展。
DOI：
10.1158/1078-0432.ccr-13-2407
发表时间：
2014-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cui J;Shi M;Xie D;Wei D;Jia Z;Zheng S;Gao Y;Huang S;Xie K
通讯作者：
Xie K
影响因子：
11.2
作者：
Quan M;Cui J;Xia T;Jia Z;Xie D;Wei D;Huang S;Huang Q;Zheng S;Xie K
通讯作者：
Xie K
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Ward, Elizabeth
通讯作者：
Ward, Elizabeth
影响因子：
8
作者：
Karunarathna U;Kongsema M;Zona S;Gong C;Cabrera E;Gomes AR;Man EP;Khongkow P;Tsang JW;Khoo US;Medema RH;Freire R;Lam EW
通讯作者：
Lam EW