Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.
J Clin Invest
; 134(11)2024 Apr 30.
Article
em En
| MEDLINE
| ID: mdl-38687617
ABSTRACT
One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.
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Bases de dados:
MEDLINE
Assunto principal:
Receptores Androgênicos
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Regulação Neoplásica da Expressão Gênica
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Neoplasias de Próstata Resistentes à Castração
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2024
Tipo de documento:
Article