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EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
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 pro...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091212/ https://www.ncbi.nlm.nih.gov/pubmed/35538070 http://dx.doi.org/10.1038/s41467-022-30105-0 |
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author | Zhang, Lin Qu, Jingkun Qi, Yutao Duan, Yimin Huang, Yu-Wen Zhou, Zhifen Li, Ping Yao, Jun Huang, Beibei Zhang, Shuxing Yu, Dihua |
author_facet | Zhang, Lin Qu, Jingkun Qi, Yutao Duan, Yimin Huang, Yu-Wen Zhou, Zhifen Li, Ping Yao, Jun Huang, Beibei Zhang, Shuxing Yu, Dihua |
author_sort | Zhang, Lin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9091212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90912122022-05-12 EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation Zhang, Lin Qu, Jingkun Qi, Yutao Duan, Yimin Huang, Yu-Wen Zhou, Zhifen Li, Ping Yao, Jun Huang, Beibei Zhang, Shuxing Yu, Dihua Nat Commun Article 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. Nature Publishing Group UK 2022-05-10 /pmc/articles/PMC9091212/ /pubmed/35538070 http://dx.doi.org/10.1038/s41467-022-30105-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhang, Lin Qu, Jingkun Qi, Yutao Duan, Yimin Huang, Yu-Wen Zhou, Zhifen Li, Ping Yao, Jun Huang, Beibei Zhang, Shuxing Yu, Dihua EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title | EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title_full | EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title_fullStr | EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title_full_unstemmed | EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title_short | EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation |
title_sort | ezh2 engages tgfβ signaling to promote breast cancer bone metastasis via integrin β1-fak activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091212/ https://www.ncbi.nlm.nih.gov/pubmed/35538070 http://dx.doi.org/10.1038/s41467-022-30105-0 |
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