Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 131 Dong'an Road, Shanghai, 200032, China.
Cancer Metabolism Laboratory and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 131 Dong'an Road, Shanghai, 200032, China.
Signal Transduct Target Ther. 2020 May 29;5(1):70. doi: 10.1038/s41392-020-0168-0.
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.
胰腺导管腺癌 (PDAC) 的早期诊断效率低下，大多数患者在晚期被诊断出来。越来越多的证据表明，血浆中支链氨基酸 (BCAA) 水平升高与患胰腺癌的风险增加有关。支链氨基酸转氨酶 2 (BCAT2) 是 BCAA 分解代谢中的一种重要酶，可逆地催化 BCAA 降解的初始步骤生成支链酰基辅酶 A。在这里，我们表明 BCAT2 在赖氨酸 44 （K44）处发生乙酰化，这是一个进化上保守的残基。BCAT2 的乙酰化导致其通过泛素-蛋白酶体途径降解，并在受到 BCAA 剥夺时被刺激。cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 和 SIRT4 分别是 BCAT2 的乙酰转移酶和去乙酰化酶。CBP 和 SIRT4 与 BCAT2 结合，并根据 BCAA 的可用性来控制 K44 乙酰化水平。更重要的是，K44R 突变体促进了 BCAA 分解代谢、细胞增殖和胰腺肿瘤生长。总之，我们的研究数据揭示了 BCAT2 在 PDAC 中的一个以前未知的调节机制，并为 PDAC 的治疗提供了一个潜在的治疗靶点。
