SIX2 promotes cell plasticity via Wnt/ß-catenin signalling in androgen receptor independent prostate cancer.
Nucleic Acids Res
; 52(10): 5610-5623, 2024 Jun 10.
Article
em En
| MEDLINE
| ID: mdl-38554106
ABSTRACT
The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide. We identified a novel regulator of cell plasticity, the homeobox transcription factor SIX2, whose motif is enriched in accessible chromatin regions after treatment. Depletion of SIX2 in androgen-independent PC-3 prostate cancer cells induced a switch from a stem-like to an epithelial state, resulting in reduced cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects were mediated through the downregulation of the Wnt/ß-catenin signalling pathway and subsequent reduction of nuclear ß-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Feniltioidantoína
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Neoplasias da Próstata
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Benzamidas
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Receptores Androgênicos
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Proteínas de Homeodomínio
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Beta Catenina
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Via de Sinalização Wnt
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Plasticidade Celular
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Nitrilas
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article