METTL14 attenuates cancer stemness by suppressing ATF5/WDR74/β-catenin axis in gastric cancer.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-11-04 DOI:10.1111/cas.16381
Peiling Zhang, Hong Xiang, Qian Peng, Lujuan Ma, Chengyin Weng, Guolong Liu, Lin Lu
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Abstract

Stemness is a key factor contributing to treatment failure in gastric cancer (GC). Methyltransferase-like 14 (METTL14) has been linked to various cancers, though its specific role in regulating stemness in GC remains undefined. In this study, we assessed METTL14 expression levels in GC tissues using public datasets and clinical specimens and investigated its impact on cell proliferation, metastasis, and stemness both in vitro and in vivo. Through m6A RNA immunoprecipitation (MeRIP) and luciferase reporter assays, we identified downstream targets of METTL14. Rescue assays were performed to examine whether METTL14 overexpression could reverse stemness in GC. We also explored the underlying mechanisms using chromatin immunoprecipitation (ChIP) and western blot analysis, focusing on the role of ATF5 and the upstream regulation of METTL14. Our findings show that lower METTL14 expression is associated with poorer overall survival in GC patients. Functionally, METTL14 knockdown enhanced stemness traits in GC cells. Mechanistically, METTL14 facilitated m6A modification, promoting the degradation of ATF5 mRNA. Overexpression of ATF5 reversed the stemness inhibition caused by METTL14 overexpression by increasing WDR74 transcription and enhancing β-catenin nuclear translocation. Furthermore, histone H3 lactylation at Lys18 was found to upregulate METTL14 expression. In conclusion, METTL14 knockdown promotes stemness in GC by mediating m6A modification of ATF5 mRNA, which activates the WDR74/β-catenin axis, making METTL14 a potential therapeutic target for gastric cancer treatment.

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METTL14通过抑制胃癌中的ATF5/WDR74/β-catenin轴减轻癌症干性。
干细胞是导致胃癌(GC)治疗失败的一个关键因素。甲基转移酶样14(METTL14)与多种癌症有关,但它在调节胃癌干性中的具体作用仍未确定。在这项研究中,我们利用公共数据集和临床标本评估了METTL14在GC组织中的表达水平,并研究了它在体外和体内对细胞增殖、转移和干性的影响。通过m6A RNA免疫沉淀(MeRIP)和荧光素酶报告实验,我们确定了METTL14的下游靶标。我们还进行了拯救试验,以检验 METTL14 的过表达是否能逆转 GC 的干性。我们还利用染色质免疫沉淀(ChIP)和Western印迹分析探讨了其潜在机制,重点研究了ATF5的作用和METTL14的上游调控。我们的研究结果表明,METTL14的低表达与GC患者较差的总生存率有关。在功能上,METTL14的敲除增强了GC细胞的干性特征。从机理上讲,METTL14有助于m6A修饰,促进ATF5 mRNA的降解。ATF5的过表达通过增加WDR74的转录和增强β-catenin的核转位,逆转了METTL14过表达导致的干性抑制。此外,研究还发现组蛋白H3在Lys18处的乳酰化能上调METTL14的表达。总之,METTL14基因敲除通过介导ATF5 mRNA的m6A修饰,激活WDR74/β-catenin轴,从而促进GC的干性,使METTL14成为治疗胃癌的潜在靶点。
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 Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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