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N-乙酰基转移酶 10 通过 N4-乙酰化和稳定铁死亡抑制蛋白 1（FSP1）mRNA 抑制铁死亡来促进结肠癌的进展。

N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA.

机构信息

Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, P. R. China.

Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, 213003, P. R. China.

出版信息

Cancer Commun (Lond). 2022 Dec;42(12):1347-1366. doi: 10.1002/cac2.12363. Epub 2022 Oct 8.

DOI:10.1002/cac2.12363
PMID:36209353
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9759759/
Abstract

BACKGROUND

N-acetyltransferase 10 (NAT10) is the only enzyme known to mediate the N4-acetylcytidine (ac4C) modification of mRNA and is crucial for mRNA stability and translation efficiency. However, its role in cancer development and prognosis has not yet been explored. This study aimed to examine the possible role of NAT10 in colon cancer.

METHODS

The expression levels of NAT10 were evaluated by immunohistochemical analyses with a colon cancer tissue microarray, and its prognostic value in patients was further analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines. Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus. The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle, and ferroptosis assays. Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo. Dot blotting, acetylated RNA immunoprecipitation-qPCR, and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.

RESULTS

NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines. This increased NAT10 expression was associated with shorter patient survival. Knockdown of NAT10 in two colon cancer cell lines (HT-29 and LoVo) impaired the proliferation, migration, invasion, tumor formation and metastasis of these cells, whereas overexpression of NAT10 promoted these abilities. Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1 (FSP1) in HT-29 and LoVo cells. In these cells, FSP1 mRNA was found to be modified by ac4C acetylation, and this epigenetic modification was associated with the inhibition of ferroptosis.

CONCLUSIONS

Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis, suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.

摘要

背景

N-乙酰基转移酶 10（NAT10）是唯一已知介导 mRNA N4-乙酰胞苷（ac4C）修饰的酶，对 mRNA 稳定性和翻译效率至关重要。然而，其在癌症发展和预后中的作用尚未得到探索。本研究旨在研究 NAT10 在结肠癌中的可能作用。

方法

使用结肠癌组织微阵列进行免疫组织化学分析评估 NAT10 的表达水平，并进一步分析其在患者中的预后价值。使用定量实时聚合酶链反应（qRT-PCR）和 Western blot 分析采集的结肠癌组织和细胞系中 NAT10 的表达。使用慢病毒构建稳定的 NAT10 敲低和 NAT10 过表达结肠癌细胞系。体外通过细胞计数试剂盒-8（CCK-8）、划痕愈合、Transwell、细胞周期和铁死亡测定分析 NAT10 在结肠癌细胞系中的生物学功能。体内使用异种移植模型分析 NAT10 对结肠癌细胞肿瘤发生和转移的影响。点印迹、乙酰化 RNA 免疫沉淀-qPCR 和 RNA 稳定性分析用于探索 NAT10 在结肠癌进展中发挥作用的机制。

结果

NAT10 在结肠癌组织和各种结肠癌细胞系中上调。这种增加的 NAT10 表达与患者生存时间缩短有关。在两种结肠癌细胞系（HT-29 和 LoVo）中敲低 NAT10 会削弱这些细胞的增殖、迁移、侵袭、肿瘤形成和转移能力，而过表达 NAT10 则促进了这些能力。进一步分析表明，NAT10 对 HT-29 和 LoVo 细胞中的 FSP1 信使 RNA 稳定性和表达具有很强的影响。在这些细胞中，FSP1 mRNA 被 ac4C 乙酰化修饰，这种表观遗传修饰与铁死亡的抑制有关。

结论

我们的研究表明，NAT10 通过影响 FSP1 mRNA 稳定性和铁死亡在结肠癌的发展中发挥关键作用，提示 NAT10 可能成为结肠癌的一个新的预后和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0c4/9759759/f341639cc022/CAC2-42-1347-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0c4/9759759/e0e3f8a660b5/CAC2-42-1347-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0c4/9759759/1025b6b95a22/CAC2-42-1347-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0c4/9759759/f341639cc022/CAC2-42-1347-g004.jpg

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