PAK4 phosphorylating RUNX1 promotes ERα-positive breast cancer-induced osteolytic bone destruction
PAK4 phosphorylating RUNX1 promotes ERα-positive breast cancer-induced osteolytic bone destruction
复制标题
PAK4 磷酸化 RUNX1 促进 ERα 阳性乳腺癌诱导的溶骨性骨破坏
DOI：
10.7150/ijbs.47225
复制
发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Li, Feng
中科院分区：
文献类型：
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作者：
Tang, Lina;Gao, Yunling;Li, Feng
核PAK 4在ER α阳性乳腺癌溶骨性骨破坏中的生物学功能尚不清楚。在这里，我们发现核PAK 4通过磷酸化RUNX 1促进破骨细胞生成和肿瘤诱导的骨质溶解。我们发现，核PAK 4相互作用，并磷酸化RUNX 1在Thr-207，诱导其从细胞核定位到细胞质，并影响与SIN 3A/HDAC 1和PRMT 1的直接相互作用。此外，我们揭示了PAK 4在Thr-207处的RUNX 1磷酸化通过靶向与破骨细胞分化和成熟相关的下游基因促进溶骨性骨破坏。重要的是，我们验证了当核PAK 4在乳腺癌骨转移组织中呈阳性时，RUNX 1亚细胞定位的变化。在功能上，我们证明了RUNX 1磷酸化促进溶骨性骨成熟和ER α阳性乳腺癌诱导的溶骨性骨损伤的小鼠模型原位乳腺癌骨转移。我们的研究结果表明PAK 4可以成为ER α阳性乳腺癌溶骨性骨破坏的治疗靶点。
The biological function of nuclear PAK4 in ER alpha-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 ER alpha-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 ER alpha-positive breast cancer osteolytic bone destruction.