EZH2 engages TGFß signaling to promote breast cancer bone metastasis via integrin ß1-FAK activation.
Nat Commun
; 13(1): 2543, 2022 05 10.
Article
em En
| MEDLINE
| ID: mdl-35538070
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 (TGFß) 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 ß1. Integrin ß1 activates focal adhesion kinase (FAK), which phosphorylates TGFß receptor type I (TGFßRI) at tyrosine 182 to enhance its binding to TGFß receptor type II (TGFßRII), thereby activating TGFß 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 ß1-FAK axis cooperates with the TGFß signaling pathway to promote bone metastasis of breast cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ósseas
/
Neoplasias da Mama
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Fator de Crescimento Transformador beta
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Integrina beta1
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Proteína-Tirosina Quinases de Adesão Focal
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Quinase 1 de Adesão Focal
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Proteína Potenciadora do Homólogo 2 de Zeste
Limite:
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2022
Tipo de documento:
Article