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Oncogene

Oncogene

IF: 7.3
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METTL3-mediated N6-methyladenosine modification of STAT5A promotes gastric cancer progression by regulating KLF4

Published:15 June 2024 DOI: 10.1038/s41388-024-03085-2 PMID: 38879589
Yichen Zang, Zhuangfei Tian, Dandan Wang, Yaxuan Li, Wenhui Zhang, Cunying Ma, Zhenzhi Liao, Wenrong Gao, Lilin Qian, Xia Xu, Jihui Jia, Zhifang Liu

Abstract

N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification in eukaryotes and plays a pivotal regulatory role in various aspects of RNA fate determination, such as mRNA stability, alternative splicing, and translation. Dysregulation of the critical m6A methyltransferase METTL3 is implicated in tumorigenesis and development. Here, this work showed that METTL3 is upregulated in gastric cancer tissues and is associated with poor prognosis. METTL3 methylates the A2318 site within the coding sequence (CDS) region of STAT5A. IGF2BP2 recognizes and binds METTL3-mediated m6A modification of STAT5A through its GXXG motif in the KH3 and KH4 domains, leading to increased stability of STAT5A mRNA. In addition, both METTL3 and IGF2BP2 are positively correlated with STAT5A in human gastric cancer tissue samples. Helicobacter pylori infection increased the expression level of METTL3 in gastric cancer cells, thereby leading to the upregulation of STAT5A. Functional studies indicated that STAT5A overexpression markedly enhances the proliferation and migration of GC cells, whereas STAT5A knockdown has inhibitory effects. Further nude mouse experiments showed that STAT5A knockdown effectively inhibits the growth and metastasis of gastric cancer in vivo. Moreover, as a transcription factor, STAT5A represses KLF4 transcription by binding to its promoter region. The overexpression of KLF4 can counteract the oncogenic impact of STAT5A. Overall, this study highlights the crucial role of m6A in gastric cancer and provides potential therapeutic targets for gastric cancer.

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Sincalide 25126-32-3 C49H62N10O16S3 395 suppliers $75.00-$8505.00
Sincalide 25126-32-3 C49H62N10O16S3 395 suppliers $75.00-$8505.00
Sincalide 25126-32-3 C49H62N10O16S3 395 suppliers $75.00-$8505.00
Sincalide 25126-32-3 C49H62N10O16S3 395 suppliers $75.00-$8505.00

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