EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation

Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang and Dihua Yu ()
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Lin Zhang: The University of Texas MD Anderson Cancer Center
Jingkun Qu: The University of Texas MD Anderson Cancer Center
Yutao Qi: The University of Texas MD Anderson Cancer Center
Yimin Duan: The University of Texas MD Anderson Cancer Center
Yu-Wen Huang: The University of Texas MD Anderson Cancer Center
Zhifen Zhou: The University of Texas MD Anderson Cancer Center
Ping Li: The University of Texas MD Anderson Cancer Center
Jun Yao: The University of Texas MD Anderson Cancer Center
Beibei Huang: The University of Texas MD Anderson Cancer Center
Shuxing Zhang: MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences
Dihua Yu: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30105-0

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