HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer.
Nat Genet
; 54(5): 670-683, 2022 05.
Article
en En
| MEDLINE
| ID: mdl-35468964
ABSTRACT
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Proteínas de Homeodominio
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Lipogénesis
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Histona Desacetilasas
Límite:
Humans
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Male
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos