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.
Highlights
branched-chain amino acids (BCAAs) are the most hydrophobic and essential amino acids for protein synthesis and molecular signals.[1]
All three BCAAs are reversibly transaminated by branched-chain amino acid transaminase 1/2 (BCAT1/2) to form branched-chain α-keto acid (BCKA), and BCKA is oxidatively decarboxylated by the branched-chain keto-acid dehydrogenase (BCKDH) complex
The results showed that Branched-chain amino acid transaminase 2 (BCAT2) was acetylated, and its acetylation level was increased ~2.1-fold after treatment with nicotinamide (NAM), an inhibitor of the sirtuin (SIRT) family of deacetylases, and trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs) I, II, and IV (Fig. 1b)
Summary
BCAAs (leucine, isoleucine, and valine) are the most hydrophobic and essential amino acids for protein synthesis and molecular signals.[1] Circulating levels of BCAAs are tightly regulated. All three BCAAs are reversibly transaminated by branched-chain amino acid transaminase 1/2 (BCAT1/2) to form branched-chain α-keto acid (BCKA), and BCKA is oxidatively decarboxylated by the branched-chain keto-acid dehydrogenase (BCKDH) complex. The final metabolites enter the TCA cycle for energy production. BCAT1 encodes a cytoplasmic protein that is primarily expressed in the brain, while BCAT2 encodes a mitochondrial protein that is ubiquitously expressed in all organs (except hepatocytes).[2] BCAT2 reversibly catalyzes the initial step of BCAA catabolism to produce BCKA and glutamate
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