Abstract：
Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
摘要：
肌动蛋白结合蛋白1(Fascin)在多种癌症中高表达,包括食管鳞状细胞癌（ESCC），作为一种重要的致癌蛋白，并通过捆绑F-肌动蛋白促进癌细胞的迁移和侵袭，以促进丝状和invadopodia的形成。然而,目前尚不清楚Fascin的功能如何在癌细胞中被乙酰化调节。这里,在ESCC细胞中，组蛋白乙酰转移酶KAT8催化Fascin赖氨酸41（K41）乙酰化，抑制Fascin介导的F-肌动蛋白成束以及丝足和invadopodia的形成。此外，NAD依赖的蛋白质去乙酰化酶sirtuin（SIRT）7介导的Fascin-K41的去乙酰化增强了丝状伪足和invadopodia的形成，促进ESCC细胞的迁移和侵袭。临床上,对ESCC患者的癌组织和癌旁组织样本的分析表明，有淋巴结转移的患者的癌组织中的Fascin-K41乙酰化程度低于无淋巴结转移的患者，和低水平的Fascin-K41乙酰化与ESCC患者预后较差相关。重要的是,K41乙酰化显著阻断NP-G2-044，目前正在临床评估的Fascin抑制剂之一，表明NP-G2-044可能更适合Fascin-K41乙酰化水平低的患者，但不适用于Fascin-K41乙酰化水平高的患者。©2024英国和爱尔兰病理学会。由JohnWiley&Sons出版,Ltd.
