DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3ß and WEE1.
Mol Cell
; 79(6): 1008-1023.e4, 2020 09 17.
Article
em En
| MEDLINE
| ID: mdl-32871104
ABSTRACT
TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3ß and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3ß inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3ß signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Proteínas Tirosina Quinases
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Proteínas de Fusão Oncogênica
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Proteínas de Ciclo Celular
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PTEN Fosfo-Hidrolase
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Glicogênio Sintase Quinase 3 beta
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos