Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth.
Signal Transduct Target Ther
; 5(1): 70, 2020 05 29.
Article
en En
| MEDLINE
| ID: mdl-32467562
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is well-known for inefficient early diagnosis, with most patients diagnosed at advanced stages. Increasing evidence indicates that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with an increased risk of pancreatic cancer. Branched-chain amino acid transaminase 2 (BCAT2) is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain acyl-CoA. Here, we show that BCAT2 is acetylated at lysine 44 (K44), an evolutionarily conserved residue. BCAT2 acetylation leads to its degradation through the ubiquitin-proteasome pathway and is stimulated in response to BCAA deprivation. cAMP-responsive element-binding (CREB)-binding protein (CBP) and SIRT4 are the acetyltransferase and deacetylase for BCAT2, respectively. CBP and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA availability. More importantly, the K44R mutant promotes BCAA catabolism, cell proliferation, and pancreatic tumor growth. Collectively, the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Pancreáticas
/
Proteínas Gestacionales
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Antígenos de Histocompatibilidad Menor
/
Proteolisis
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Aminoácidos de Cadena Ramificada
/
Transaminasas
/
Proteínas de Neoplasias
Tipo de estudio:
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Signal Transduct Target Ther
Año:
2020
Tipo del documento:
Article
País de afiliación:
China