The biological function of nuclear PAK4 in ERα-positive breast cancer osteolytic bone destruction remains unclear. Here, we find that the nuclear PAK4 promotes osteoclastogenesis and tumor-induced osteolysis via phosphorylating RUNX1. We show that nuclear PAK4 interacts with and phosphorylates RUNX1 at Thr-207, which induces its localization from the nucleus to the cytoplasm and influences direct interaction with SIN3A/HDAC1 and PRMT1. Furthermore, we reveal that RUNX1 phosphorylation by PAK4 at Thr-207 promotes osteolytic bone destruction via targeting downstream genes related to osteoclast differentiation and maturation. Importantly, we verify changes in RUNX1 subcellular localization when nuclear PAK4 is positive in breast cancer bone metastasis tissues. Functionally, we demonstrate that RUNX1 phosphorylation promotes osteolytic bone maturation and ERα-positive breast cancer-induced osteolytic bone damage in the mouse model of orthotopic breast cancer bone metastasis. Our results suggest PAK4 can be a therapeutic target for ERα-positive breast cancer osteolytic bone destruction.

中文翻译：

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PAK4 磷酸化 RUNX1 促进 ERα 阳性乳腺癌诱导的溶骨性骨破坏。


核PAK4在ERα阳性乳腺癌溶骨性骨破坏中的生物学功能仍不清楚。在这里，我们发现核 PAK4 通过磷酸化 RUNX1 促进破骨细胞生成和肿瘤诱导的骨溶解。我们发现核 PAK4 与 RUNX1 Thr-207 相互作用并磷酸化 RUNX1，从而诱导其从细胞核定位到细胞质，并影响与 SIN3A/HDAC1 和 PRMT1 的直接相互作用。此外，我们发现 PAK4 在 Thr-207 处磷酸化 RUNX1 通过靶向与破骨细胞分化和成熟相关的下游基因来促进溶骨性骨质破坏。重要的是，我们验证了乳腺癌骨转移组织中核 PAK4 呈阳性时 RUNX1 亚细胞定位的变化。在功能上，我们证明 RUNX1 磷酸化可促进原位乳腺癌骨转移小鼠模型中的溶骨性骨成熟和 ERα 阳性乳腺癌诱导的溶骨性骨损伤。我们的结果表明 PAK4 可以成为 ERα 阳性乳腺癌溶骨性骨质破坏的治疗靶点。