RESUMEN

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.

Asunto(s)

Aminoácidos de Cadena Ramificada , Antígenos de Histocompatibilidad Menor , Proteínas de Neoplasias , Neoplasias Pancreáticas , Proteínas Gestacionales , Proteolisis , Transaminasas , Acetilación , Aminoácidos de Cadena Ramificada/genética , Aminoácidos de Cadena Ramificada/metabolismo , Línea Celular Tumoral , Células HEK293 , Humanos , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Transaminasas/genética , Transaminasas/metabolismo