Mutated SPOP E3 Ligase Promotes 17ßHSD4 Protein Degradation to Drive Androgenesis and Prostate Cancer Progression.
Cancer Res
; 81(13): 3593-3606, 2021 07 01.
Article
en En
| MEDLINE
| ID: mdl-33762355
ABSTRACT
Molecular mechanisms underlying intratumoral androgenesis and aberrant androgen receptor (AR) activation in prostate cancer remain poorly understood. Here we demonstrate that ectopic expression of the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger domain protein (SPOP) stabilizes 17ßHSD4. SPOP bound a functional substrate-binding consensus (SBC) motif 315RATST319 in 17ßHSD4 and promoted nondegradable K27- and K29-linked polyubiquitination of 17ßHSD4. The effect of SPOP was antagonized by serum- and glucocorticoid kinase-3 (SGK3)-mediated phosphorylation of serine 318 (S318) in the SBC and S318 phosphorylation-dependent binding of SKP2 E3 ligase and subsequent K48-linked polyubiquitination and proteasomal degradation of 17ßHSD4. Prostate cancer-associated SPOP mutations impaired the SPOP-17ßHSD4 interaction, caused 17ßHSD4 protein destruction in prostate cancer cells in culture and patient specimens, and increased testosterone production and prostate cancer cell growth in vitro and in mouse models. Thus, we have identified SPOP and SKP2 as two essential E3 ubiquitin ligases that exert opposite effects on 17ßHSD4 protein degradation and intratumoral androgenesis in prostate cancer cells. We further demonstrate that SPOP mutations or SKP2 overexpression contribute to prostate cancer progression by decreasing 17ßHSD4 expression and increasing intratumoral androgen synthesis. SIGNIFICANCE:
This study reveals a novel mechanism of aberrant AR activation in SPOP-mutated prostate cancer and uncovers putative biomarkers for effective treatment by AR-targeted therapies.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Proteínas Represoras
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Proteínas Nucleares
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Receptores Androgénicos
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Regulación Neoplásica de la Expresión Génica
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Proteína-2 Multifuncional Peroxisomal
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Andrógenos
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Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
China