Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth
Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth
复制标题
乙酰化促进 BCAT2 降解，抑制 BCAA 分解代谢和胰腺癌生长
DOI：
10.1038/s41392-020-0168-0
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发表时间：
2020-05-29
影响因子：
39.3
通讯作者：
Lei, Qun-Ying
中科院分区：
文献类型：
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作者：
Lei, Ming-Zhu;Li, Xu-Xu;Lei, Qun-Ying
胰腺导管腺癌（PDAC）是众所周知的低效率的早期诊断，与大多数患者在晚期诊断。越来越多的证据表明，支链氨基酸（BCAA）的血浆水平升高与胰腺癌的风险增加有关。支链氨基酸转氨酶2（BCAT 2）是支链氨基酸催化剂中的一个重要酶，可逆地催化支链氨基酸降解为支链酰基辅酶A的初始步骤。在这里，我们表明，BCAT 2是乙酰化的赖氨酸44（K44），一个进化上保守的残基。BCAT 2乙酰化导致其通过泛素-蛋白酶体途径降解，并在BCAA剥夺时受到刺激。cAMP反应元件结合蛋白（CBP）和SIRT 4分别是BCAT 2的乙酰转移酶和脱乙酰酶。CBP和SIRT 4与BCAT 2结合，并控制K44乙酰化水平以响应BCAA的可用性。更重要的是，K44 R突变体促进BCAA分解代谢、细胞增殖和胰腺肿瘤生长。总的来说，我们的研究数据揭示了BCAT 2在PDAC中的一种以前未知的调节机制，并为PDAC治疗提供了一个潜在的治疗靶点。
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.