HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration.
Nucleic Acids Res
; 48(6): 2912-2923, 2020 04 06.
Article
en En
| MEDLINE
| ID: mdl-31970414
ABSTRACT
NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-ß signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-ß signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-ß signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-ß signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-ß signaling related diseases.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
Movimiento Celular
/
Sirtuinas
/
Proteína smad3
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Proteína Smad4
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Histona Desacetilasas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2020
Tipo del documento:
Article
País de afiliación:
China