Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a PRMT1-DDX3 axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates PINK1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer.

中文翻译：

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PRMT1对DDX3的精氨酸甲基化介导线粒体稳态促进乳腺癌转移


线粒体动力学和代谢失调在肿瘤发生中发挥重要作用。转移肿瘤细胞主要利用线粒体代谢，代谢重编程的调节因子可能为诊断癌症转移提供可靠的生物标志物。在这里，我们确定了一个 PRMT1-DDX3 轴，它通过协调线粒体生物发生和线粒体自噬来促进乳腺癌转移，以确保线粒体质量控制。从机制上讲，PRMT1 诱导 DDX3 的精氨酸甲基化，从而增强其蛋白质稳定性并防止蛋白酶体降解。 DDX3 通过易位至线粒体来介导线粒体稳态，在线粒体中促进 PINK1 翻译以响应线粒体应激。抑制 DDX3 可抑制线粒体生物合成和线粒体自噬，从而降低癌症干性和转移特性。总体而言，这项研究揭示了 PRMT1-DDX3 轴调节线粒体稳态以支持乳腺癌转移的机制，提出了针对代谢脆弱性治疗转移性乳腺癌的策略。