TY - JOUR
T1 - EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
AU - Zhang, Lin
AU - Qu, Jingkun
AU - Qi, Yutao
AU - Duan, Yimin
AU - Huang, Yu Wen
AU - Zhou, Zhifen
AU - Li, Ping
AU - Yao, Jun
AU - Huang, Beibei
AU - Zhang, Shuxing
AU - Yu, Dihua
N1 - Funding Information:
We thank members of the Yu’s laboratory for insightful discussions. We thank D. Norwood, the Department of Scientific Publications of MD Anderson Cancer Center for article revision. This work was supported by National Institutes of Health (NIH) grants R01CA184836 (D.Y.), R01 CA208213 (D.Y.), and R01CA231149 (D.Y.), the METAvivor grants 56675 and 58284 (D.Y.), and NIH Cancer Center Support Grant P30CA016672 to MD Anderson Cancer Center (Functional Genomics Core, Flow Cytometry and Cellular Imaging resource, Advanced Technology Genomics Core, Research Histology Core Laboratory, Cytogenetics and Cell Authentication Core, Functional Proteomics Reverse Phase Protein Array Core, and Research Animal Support Facility-Houston). J.Q. received fellowship from China Scholarship Council 201706280072. Y.-W.H. received fellowship from the Ministry of Education, Taiwan: The International Co-cultivation of Talent Program. D.Y. is the Hubert L. and Olive Stringer Distinguished Chair in Basic Science at MD Anderson. Mass spectrum is performed at and supported in part by the Clinical and Translational Proteomics Service Center at the University of Texas Health Science Center.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-30105-0
DO - 10.1038/s41467-022-30105-0
M3 - Article
C2 - 35538070
AN - SCOPUS:85129882285
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2543
ER -