FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors

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)-beta 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 TGF beta/Atk/GSK3 beta/ubiquitin pathways. Interestingly, the GSK3 beta inhibitor could abrogate the role of FHL3 in the regulation of snail1 and twist1 expression, which implied that GSK3 beta plays a pivotal role in the FHL3-mediated EMT process. Furthermore, we found that FHL3 can directly bind to GSK3 beta, which weakened the interaction between GSK3 beta and snail1/twist1. We also found that the LIM-3 domain of FHL3 was required for the binding of FHL3 to GSK3 beta. Collectively, our study implied that FHL3, as a binding partner of GSK3 beta, promoted tumor metastasis in PDAC through inhibiting the ubiquitin-degradation of snail1 and twist1.