NAT10-mediated ac4C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell carcinoma by attenuating YWHAE-driven cytoplasmic retention of YAP1

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications Pub Date : 2024-02-26 DOI:10.1002/cac2.12523

Daojia Miao, Jian Shi, Qingyang Lv, Diaoyi Tan, Chuanyi Zhao, Zhiyong Xiong, Xiaoping Zhang

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引用次数: 0

Abstract

Background

Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma (ccRCC). N-acetyltransferase 10 (NAT10) is known to catalyze N4-acetylcytidine (ac⁴C) modification of mRNA and participate in many cellular processes. However, its role in the lymphangiogenic process of ccRCC has not been reported. This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis, providing valuable insights into potential therapeutic targets for intervention.

Methods

ac⁴C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples. Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC. Mechanistic insights were gained through a combination of RNA sequencing, mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, and site-specific mutation analyses.

Results

We found that ac⁴C modification and NAT10 expression levels increased in ccRCC. NAT10 promoted tumor progression and lymphangiogenesis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator (YAP1). Subsequently, we identified ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) as the functional target of NAT10, and its upregulation in ccRCC was caused by NAT10-mediated ac⁴C modification. Mechanistic analyses demonstrated that ANKZF1 interacted with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) to competitively inhibit cytoplasmic retention of YAP1, leading to transcriptional activation of pro-lymphangiogenic factors.

Conclusions

These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.

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NAT10 介导的 ac4 C 修饰的 ANKZF1 通过减弱 YWHAE 驱动的 YAP1 胞质滞留，促进透明细胞肾细胞癌的肿瘤进展和淋巴管生成。

背景：淋巴转移是最常见的转移途径之一，预示着透明细胞肾细胞癌（ccRCC）的不良预后。众所周知，N-乙酰转移酶 10（NAT10）可催化 mRNA 的 N4-乙酰胞苷（ac4 C）修饰，并参与许多细胞过程。然而，它在ccRCC淋巴管生成过程中的作用尚未见报道。本研究旨在阐明NAT10在ccRCC淋巴管生成过程中的作用，为潜在的治疗靶点提供有价值的见解。方法：利用公共数据库和临床样本评估ccRCC中ac4 C修饰和NAT10的表达水平。功能研究包括在细胞和小鼠模型中操纵 NAT10 的表达，以研究其在 ccRCC 中的作用。通过结合 RNA 测序、质谱分析、共免疫沉淀、RNA 免疫沉淀、免疫荧光和位点特异性突变分析，我们获得了对机理的深入了解：结果：我们发现ac4 C修饰和NAT10在ccRCC中的表达水平升高。NAT10通过增强Yes1相关转录调节因子（YAP1）的核导入促进了ccRCC的肿瘤进展和淋巴管生成。随后，我们发现杏仁蛋白重复和锌指肽基tRNA水解酶1（ANKZF1）是NAT10的功能靶标，其在ccRCC中的上调是由NAT10介导的ac4 C修饰引起的。机理分析表明，ANKZF1与酪氨酸3-单氧化酶/色氨酸5-单氧化酶活化蛋白epsilon（YWHAE）相互作用，竞争性抑制YAP1的细胞质滞留，导致促淋巴管生成因子的转录激活：这些结果表明了NAT10介导的乙酰化在ccRCC中的促癌作用，并确定了NAT10/ANKZF1/YAP1轴是ccRCC中涉及肿瘤进展和淋巴管生成的一个未被充分报道的通路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

25.50

自引率

4.30%

发文量

153

审稿时长

4 weeks

期刊介绍： Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.