Department of Urology, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncogene. 2024 Nov;43(47):3426-3441. doi: 10.1038/s41388-024-03180-4. Epub 2024 Sep 28.
Dysregulated N-methyladenosine (mA) modification has been associated with breast cancer pathogenesis. Hypoxia which characterizes solid tumors is known to reprogram the mA epitranscriptome, but the underlying mechanisms of how this process contributes to breast cancer progression remain poorly understood. Through integrative analyses of mA-RIP sequencing and RNA sequencing databases, we reveal a cluster of mRNAs with upregulated mA methylation and expression under hypoxia, that are enriched by many oncogenic pathways, including PI3K-Akt signaling. Furthermore, we identify the mRNA, RIPOR3, as a target of METTL3-mediated mA methylation in response to hypoxia. We find that mA methylation stabilizes RIPOR3, increasing its protein expression in a METTL3 catalytic activity-dependent manner, and consequently driving breast tumor growth and metastasis. RIPOR3 is found to be overexpressed in breast cancer cell lines and tumor tissues from breast cancer patients, in whom elevated RIPOR3 is associated with a worse prognosis. Mechanistically, we show that RIPOR3 interacts with EGFR and is essential for the PI3K-Akt pathway activation. In conclusion, we identify RIPOR3 as a hypoxia-stabilized oncogenic driver via METTL3-mediated mA methylation, thus provide a potential therapeutic target for breast cancer.
N6-甲基腺苷（m6A）修饰失调与乳腺癌的发病机制有关。已知实体瘤中的缺氧会重新编程 mA 表转录组，但这一过程如何促进乳腺癌进展的潜在机制仍知之甚少。通过对 mA-RIP 测序和 RNA 测序数据库的综合分析，我们揭示了一组在缺氧下 mA 甲基化和表达上调的 mRNA，这些 mRNA 富集了许多致癌途径，包括 PI3K-Akt 信号通路。此外，我们确定了 mRNA RIPOR3 是 METTL3 介导的 mA 甲基化对缺氧反应的靶标。我们发现 mA 甲基化稳定了 RIPOR3，以 METTL3 催化活性依赖的方式增加其蛋白质表达，从而促进乳腺肿瘤的生长和转移。在乳腺癌细胞系和乳腺癌患者的肿瘤组织中发现 RIPOR3 过表达，其中 RIPOR3 水平升高与预后不良相关。从机制上讲，我们表明 RIPOR3 与 EGFR 相互作用，是 PI3K-Akt 通路激活所必需的。总之，我们确定 RIPOR3 是一种通过 METTL3 介导的 mA 甲基化稳定的致癌驱动因子，因此为乳腺癌提供了一个潜在的治疗靶点。
