FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors
FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors
复制标题
FHL3通过阻止EMT相关转录因子泛素化降解促进胰腺癌侵袭和转移
DOI：
10.18632/aging.102564
复制
发表时间：
2020-01-15
期刊：
影响因子：
5.2
通讯作者：
Wu, Yulian
中科院分区：
文献类型：
--
作者：
Li, Pengping;Cao, Guodong;Wu, Yulian
胰腺导管腺癌（PDAC）具有较强的侵袭性和转移性，是一种难治性肿瘤。上皮间质转化（EMT）是肿瘤侵袭和转移的关键驱动力。四个半LIM结构域（FHL）家族参与调节转化生长因子（TGF）-β和Ras信号通路，可能控制EMT过程。在这项研究中，我们发现四个半LIM结构域3（FHL 3）的高表达预示着PDAC的预后不良。FHL 3的降低通过阻断TGFβ/Atk/GSK 3 β/ubiquitin通路改变EMT表型。有趣的是，GSK 3 β抑制剂可以消除FHL 3在调节snail 1和twist 1表达中的作用，这意味着GSK 3 β在FHL 3介导的EMT过程中起关键作用。此外，我们还发现FHL 3可以直接与GSK 3 β结合，从而减弱了GSK 3 β与snail 1/twist 1的相互作用。我们还发现FHL 3的LIM-3结构域是FHL 3与GSK 3 β结合所必需的。综上所述，FHL 3作为GSK 3 β的结合伴侣，通过抑制snail 1和twist 1的泛素降解，促进PDAC的肿瘤转移。
Pancreatic ductal adenocarcinoma (PDAC) is intractable due to its strong invasiveness and metastatic ability. Epithelial-mesenchymal transition (EMT) is the pivotal driver of tumor invasion and metastasis. The four-and-a-half LIM domain (FHL) family is involved in regulating transforming growth factor (TGF)-β and Ras signaling, which might control the EMT process. In this study, we found that higher expression of four-and-a-half LIM domains 3 (FHL3) predicted poor prognosis in PDAC. The decreasing of FHL3 changed the EMT phenotype by blocking the TGFβ/Atk/GSK3β/ubiquitin pathways. Interestingly, the GSK3β inhibitor could abrogate the role of FHL3 in the regulation of snail1 and twist1 expression, which implied that GSK3β plays a pivotal role in the FHL3-mediated EMT process. Furthermore, we found that FHL3 can directly bind to GSK3β, which weakened the interaction between GSK3β and snail1/twist1. We also found that the LIM-3 domain of FHL3 was required for the binding of FHL3 to GSK3β. Collectively, our study implied that FHL3, as a binding partner of GSK3β, promoted tumor metastasis in PDAC through inhibiting the ubiquitin-degradation of snail1 and twist1.