Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Nat Commun. 2022 May 10;13(1):2543. doi: 10.1038/s41467-022-30105-0.
Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer.
骨转移发生在 50-70%的晚期乳腺癌患者中，因此需要有效的治疗方法。增强子结合蛋白 2（EZH2）的表达与乳腺癌转移相关，但它在骨转移中的作用尚未得到充分研究。在这里，我们报告 EZH2 通过调节转化生长因子 β（TGFβ）信号促进乳腺癌溶骨性转移。EZH2 诱导癌细胞增殖和破骨细胞成熟，而 EZH2 敲低则减少体内骨转移的发生率和生长。在机制上，EZH2 转录增加了编码整合素 β1（ITGB1）的基因。整合素 β1 激活粘着斑激酶（FAK），FAK 将 TGFβ 受体 I（TGFβRI）上的酪氨酸 182 磷酸化，以增强其与 TGFβ 受体 II（TGFβRII）的结合，从而激活 TGFβ 信号通路。临床上可应用的 FAK 抑制剂而非 EZH2 甲基转移酶抑制剂可有效抑制体内乳腺癌骨转移。总的来说，我们发现 EZH2-整合素 β1-FAK 轴与 TGFβ 信号通路协同促进乳腺癌的骨转移。
