NAT10 相分离调控 YTHDF1 剪接促进胃癌进展

IF 12.5 1区 医学 Q1 ONCOLOGY
Songyi Liu, Chunlin Lin, Xiang Lin, Penghang Lin, Ruofan He, Xiaoyu Pan, Yan Lin, Jianxin Ye, Guangwei Zhu
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引用次数: 0

摘要

胃癌(GC)是一种侵袭性很强的恶性肿瘤,患者预后很差。NAT10 是一种乙酰转移酶,有报道称它有助于胃癌的进展。深入研究由 NAT10 驱动的潜在分子机制有助于确定治疗靶点,从而改善胃癌的治疗。在这里,我们发现 NAT10 会形成凝聚物来调节 RNA 动态并促进 GC 的进展。在 GC 患者样本中,NAT10 表达升高与预后不良、疾病晚期和转移相关。NAT10 可促进 GC 细胞的增殖、迁移和侵袭,支持患者衍生的器官组织的生长,并加速肿瘤的发展。NAT10的C端内在无序区介导了液-液相分离(LLPS),对其在GC中的肿瘤促进功能至关重要。此外,NAT10还与剪接因子SRSF2相互作用,导致其乙酰化并增加其稳定性。乙酰化的SRSF2直接与m6A阅读器YTHDF1的前mRNA结合,导致YTHDF1第4外显子跳越增强,短YTHDF1转录本上调,从而刺激GC细胞增殖和迁移。此外,YTHDF1 第 4 外显子跳越与 NAT10 和 SRSF2 的表达相关,并与 GC 患者样本中更具侵袭性的表型相关。总之,这项研究揭示了 NAT10 LLPS 在通过 SRSF2 乙酰化调节 YTHDF1 剪接以驱动 GC 进展中的作用,为了解 NAT10 的致癌机制提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression.

Gastric cancer is an aggressive malignancy with poor patient outcomes. N-Acetyltransferase 10 (NAT10) is an acetyltransferase that has been reported to contribute to gastric cancer progression. In-depth investigation into the underlying molecular mechanisms driven by NAT10 could help identify therapeutic targets to improve gastric cancer treatment. In this study, we found that NAT10 forms condensates to regulate RNA dynamics and promote gastric cancer progression. In samples of patients with gastric cancer, elevated NAT10 expression correlated with an unfavorable prognosis, advanced disease stage, and metastasis. NAT10 enhanced the proliferation, migration, and invasion of gastric cancer cells; supported the growth of patient-derived organoids; and accelerated tumor development. A C-terminal intrinsically disordered region-mediated liquid-liquid phase separation of NAT10 and was essential for its tumor-promoting function in gastric cancer. Moreover, NAT10 interacted with the splicing factor serine/arginine-rich splicing factor 2 (SRSF2), leading to its acetylation and increased stability. Acetylated SRSF2 directly bound to the pre-mRNA of the m6A reader YTHDF1, resulting in enhanced YTHDF1 exon 4 skipping and upregulation of a short YTHDF1 transcript that could stimulate gastric cancer cell proliferation and migration. Furthermore, YTHDF1 exon 4 skipping correlated with NAT10 and SRSF2 expression and was associated with a more aggressive phenotype in samples of patients with gastric cancer. Together, this study uncovers the role of NAT10 liquid-liquid phase separation in modulating YTHDF1 splicing through SRSF2 acetylation to drive gastric cancer progression, providing insights into the oncogenic mechanism of NAT10. Significance: Phase separation of NAT10 enables acetylation of SRSF2 that enhances YTHDF1 exon 4 skipping, which is a tumor-promoting axis in gastric cancer that represents potential therapeutic targets and prognostic biomarkers.

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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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