甲基转移酶样 3 (METTL3) 的表达增强会促进特定 mRNA 的 m6A 修饰，从而促进乳腺肿瘤的发生。虽然 METTL3 靶向的 mRNA 底物已得到很好的表征，但决定这些特定 mRNA 选择的因素仍然难以捉摸。本研究旨在探讨转录因子 STAT5B 在 METTL3 诱导的 m6A 修饰中的调节作用。 METTL3 与 STAT5B 特异性相互作用，以响应表皮生长因子 (EGF) 的有丝分裂刺激。染色质免疫沉淀和 CRISPR/Cas9 诱变表明，STAT5B 将 METTL3 招募到 CCND1 等基因启动子，其中 METTL3 与 RPB1 相互作用，依赖于转录延伸过程中 CDK9 介导的 RPB1 (Ser2) 磷酸化。 STAT5B 或 CDK9 的抑制和耗竭可阻止 EGF 诱导的 CCND1 m6A 修饰。 m6A 修饰后 CCND1 的翻译效率增加，从而增加细胞增殖。 STAT5B 通过增加原位小鼠模型中 CCND1 的表达来促进 METTL3 诱导的肿瘤形成。在我们的研究队列中，在高级别乳腺肿瘤中观察到 p-STAT5B 和 METTL3 表达之间呈正相关。这项研究阐明了乳腺癌细胞中 m6A 修饰特异性的新机制，从而强调了其潜在的治疗价值。版权所有 © 2024。由 Elsevier B.V. 出版。

Enhanced expression of methyltransferase-like 3 (METTL3) promotes the m6A modification of specific mRNAs, contributing to breast tumorigenesis. While the mRNA substrates targeted by METTL3 are well characterized, the factors dictating the selection of these specific mRNA remain elusive. This study aimed to examine the regulatory role of the transcription factor STAT5B in METTL3-induced m6A modification. METTL3 specifically interacts with STAT5B in response to mitogenic stimulation by epidermal growth factor (EGF). Chromatin immunoprecipitation and CRISPR/Cas9 mutagenesis showed that STAT5B recruits METTL3 to gene promoters like CCND1, where METTL3 interacts with RPB1, dependent on CDK9-mediated RPB1 (Ser2) phosphorylation during transcription elongation. Inhibition and depletion of either STAT5B or CDK9 prevented the EGF-induced m6A modification of CCND1. The translation efficiency of CCND1 was increased following m6A modification, thereby increasing cell proliferation. STAT5B facilitated METTL3-induced tumor formation by increasing CCND1 expression in an orthotopic mouse model. In our study cohort, a positive correlation was observed between p-STAT5B and METTL3 expression in high-grade breast tumors. This study elucidates a novel mechanism that underlies the specificity of m6A modification in breast cancer cells, thereby underscoring its potential therapeutic value.Copyright © 2024. Published by Elsevier B.V.