ALKBH5以m6a依赖的方式抑制未封盖WRAP53 RNA亚型的翻译，从而抑制胃癌的肿瘤发生和转移

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-01-15 DOI:10.1186/s12943-024-02223-4

Ziqi Zheng, Feizhi Lin, Baiwei Zhao, Guoming Chen, Chengzhi Wei, Xiaojiang Chen, Runcong Nie, Ruopeng Zhang, Zhoukai Zhao, Zhiwei Zhou, Yuanfang Li, Weigang Dai, Yijia Lin, Yongming Chen

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引用次数: 0

摘要

n6 -甲基腺苷（m6A）修饰在真核细胞中是一种重要的表观遗传调控因子，在肿瘤发生和癌症进展中起重要作用。然而，m6A在胃癌（GC）中调控的详细生物学功能和潜在机制尚不清楚。我们的研究发现m6A去甲基化酶ALKBH5在GC组织中明显下调，这与患者预后不良有关。功能研究表明，抑制ALKBH5表达可增强GC细胞的增殖、迁移和侵袭。从机制上讲，ALKBH5从WRAP53的5 '无帽转录本和多腺苷化转录本（UPTs）中去除m6A修饰。这种去甲基化降低了WRAP53的稳定性和翻译效率。低水平的WRAP53破坏USP6与RALBP1蛋白之间的相互作用，促进RALBP1降解，从而抑制PI3K/Akt/mTOR信号级联，最终减缓GC的进展。这些发现强调了ALKBH5介导的m6A去甲基化在抑制胃癌进展中的关键作用，以及ALKBH5作为一种有前景的生物标志物和胃癌干预治疗靶点的潜在作用。

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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ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.