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. 2024 May;263(1):74-88.
doi: 10.1002/path.6261. Epub 2024 Feb 27.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma

Da-Jia Li #  1 , Yin-Wei Cheng #  1   2 , Jin-Mei Pan #  3 , Zhen-Chang Guo  1   4 , Shao-Hong Wang  5 , Qing-Feng Huang  6 , Ping-Juan Nie  1 , Wen-Qi Shi  5 , Xiu-E Xu  1   6 , Bing Wen  1 , Jin-Ling Zhong  1 , Zhi-Da Zhang  1 , Zhi-Yong Wu  5 , Hui Zhao  1   2 , Lian-Di Liao  1   6 , Jian-Yi Wu  1 , Kai Zhang  4 , Geng Dong  3 , En-Min Li  1   7 , Li-Yan Xu  1   2   6
Affiliations

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma

Da-Jia Li et al. J Pathol. 2024 May.

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.

Keywords: Fascin; F‐actin; KAT8; SIRT7; acetylation; esophageal squamous cell carcinoma; filopodia; invadopodia; tumor metastasis.

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