Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
Department of Pathology, School of Medicine, Chosun University, Gwangju, 61452, Republic of Korea.
Cancer Lett. 2024 Oct 28;603:217215. doi: 10.1016/j.canlet.2024.217215. Epub 2024 Aug 31.
Enhanced expression of methyltransferase-like 3 (METTL3) promotes the mA 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 mA 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 mA modification of CCND1. The translation efficiency of CCND1 was increased following mA modification, thereby increasing cell proliferation. STAT5B facilitated METTL3-induced tumor formation by increasing CCND1 expression in an orthotopic mouse model. In clinical context, 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 mA modification in breast cancer cells, thereby underscoring its potential therapeutic value.
甲基转移酶样蛋白 3（METTL3）的表达增强促进了特定 mRNA 的 mA 修饰，从而促进了乳腺癌的发生。虽然 METTL3 的 mRNA 底物已经得到很好的描述，但决定这些特定 mRNA 选择的因素仍不清楚。本研究旨在研究转录因子 STAT5B 在 METTL3 诱导的 mA 修饰中的调节作用。METTL3 特异性地与 STAT5B 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 诱变显示，STAT5B 招募 METTL3 到基因启动子，如 CCND1，在那里 METTL3 与 RPB1 相互作用，这依赖于 CDK9 介导的 RPB1（Ser2）磷酸化在转录延伸过程中。STAT5B 或 CDK9 的抑制和耗竭均可阻止 EGF 诱导的 CCND1 的 mA 修饰。CCND1 的翻译效率在 mA 修饰后增加，从而增加细胞增殖。在原位小鼠模型中，STAT5B 通过增加 CCND1 的表达促进了 METTL3 诱导的肿瘤形成。在临床背景下，在高级别乳腺癌中观察到 p-STAT5B 和 METTL3 表达之间存在正相关。本研究阐明了乳腺癌细胞中 mA 修饰特异性的新机制，强调了其潜在的治疗价值。
