PDF(Pubmed)
Abstract：
It has been shown that the formation of filopodia is a key step in tumor cell metastasis, but there is limited research regarding its mechanism. In this study, we demonstrated that fatty acid synthase (FASN) promoted filopodia formation in liver cancer cells by regulating fascin actin-bundling protein 1 (FSCN1), a marker protein for filopodia. Mechanistically, on the one hand, the accumulation of FASN is caused by the enhanced deubiquitination of FASN mediated by UCHL5 (ubiquitin c-terminal hydrolase L5). In this pathway, low expression of SIAH1 (Seven in absentia homolog 1) can decrease the ubiquitination and degradation of ADRM1 (adhesion regulating molecule 1) thereby increasing its protein level, which will recruit and activate the deubiquitination enzyme UCHL5, leading to FASN undergo deubiquitination and escape from proteasomal degradation. On the other hand, the accumulation of FASN is related to its weakened ubiquitination, where SIAH1 directly acts as a ubiquitin ligase toward FASN, and low expression of SIAH1 reduces the ubiquitination and degradation of FASN. Both the two pathways are involved in the regulation of FASN in liver cancer. Our results reveal a novel mechanism for FASN accumulation due to the low expression of SIAH1 in human liver cancer and suggest an important role of FASN in filopodia formation in liver cancer cells.
摘要：
研究表明，丝足病的形成是肿瘤细胞转移的关键步骤，但是关于其机制的研究有限。在这项研究中,我们证明了脂肪酸合成酶（FASN）通过调节Fascin肌动蛋白束蛋白1（FSCN1）促进肝癌细胞中丝状伪足的形成，丝状伪足的标记蛋白。机械上,一方面,FASN的积累是由UCHL5（泛素c端水解酶L5）介导的FASN去泛素化增强引起的。在这条道路上,SIAH1的低表达（7个缺失同源物1）可以减少ADRM1（粘附调节分子1）的泛素化和降解，从而增加其蛋白质水平，这将招募和激活去泛素化酶UCHL5，导致FASN经历去泛素化和逃脱蛋白酶体降解。另一方面,FASN的积累与其泛素化减弱有关，其中SIAH1直接充当FASN的泛素连接酶，SIAH1的低表达减少了FASN的泛素化和降解。这两种途径均参与FASN在肝癌中的调控。我们的结果揭示了由于SIAH1在人肝癌中的低表达而导致的FASN积累的新机制，并暗示了FASN在肝癌细胞中丝状伪足形成中的重要作用。
