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SIAH1 缺乏通过增加 FASN 在肝癌中的积累促进了伪足的形成。

Deficiency of SIAH1 promotes the formation of filopodia by increasing the accumulation of FASN in liver cancer.

机构信息

Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.

出版信息

Cell Death Dis. 2024 Jul 29;15(7):537. doi: 10.1038/s41419-024-06929-7.

DOI:10.1038/s41419-024-06929-7
PMID:39075049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11286965/
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

已有研究表明，片状伪足的形成是肿瘤细胞转移的关键步骤，但关于其机制的研究还很有限。在本研究中，我们证明脂肪酸合酶（FASN）通过调节丝状伪足的标志性蛋白 fascin 肌动蛋白结合蛋白 1（FSCN1）促进肝癌细胞中片状伪足的形成。在机制上，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。在这条通路中，SIAH1（Seven in absentia homolog 1）的低表达可以减少 ADRM1（粘附调节分子 1）的泛素化和降解，从而增加其蛋白水平，这将招募并激活去泛素化酶 UCHL5，导致 FASN 去泛素化并逃避蛋白酶体降解。另一方面，FASN 的积累与它的泛素化减弱有关，其中 SIAH1 直接作为 FASN 的泛素连接酶，SIAH1 的低表达减少了 FASN 的泛素化和降解。这两种途径都参与了肝癌中 FASN 的调节。我们的研究结果揭示了由于人类肝癌中 SIAH1 的低表达导致 FASN 积累的新机制，并表明 FASN 在肝癌细胞中片状伪足形成中的重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/0d7e5012677a/41419_2024_6929_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/85ee3460f651/41419_2024_6929_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/72604b068683/41419_2024_6929_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/0d7e5012677a/41419_2024_6929_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/3c3da32e8784/41419_2024_6929_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/4b5d7c0f052f/41419_2024_6929_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/c1296dd0ed74/41419_2024_6929_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/dcf5282f7421/41419_2024_6929_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/fe2842599bca/41419_2024_6929_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/d6a6003f98ce/41419_2024_6929_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/fcbc938dbcd1/41419_2024_6929_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/85ee3460f651/41419_2024_6929_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/72604b068683/41419_2024_6929_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90fc/11286965/0d7e5012677a/41419_2024_6929_Fig10_HTML.jpg

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