Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression
Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression
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甲胎蛋白乙酰化促进肝细胞癌进展
DOI：
10.1016/j.canlet.2019.11.043
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发表时间：
2020-02-28
期刊：
影响因子：
9.7
通讯作者：
Zhang, Xiaowei
中科院分区：
文献类型：
--
作者：
Xue, Junhui;Cao, Zhengyi;Zhang, Xiaowei
甲胎蛋白(AFP)是一种公认的肝细胞癌的生物标志物。在此，我们研究了甲胎蛋白在体内的乙酰化状态。AFP乙酰化受乙酰基转移酶CBP和去乙酰基酶SIRT1调控。AFP在194、211和242位的乙酰化通过减少泛素化和蛋白酶体降解来增加AFP蛋白的稳定性。AFP乙酰化通过阻断与磷酸酶PTEN和促凋亡蛋白caspase-3的结合来促进其致癌作用，后者增加了增殖、迁移和侵袭的信号，并减少了细胞凋亡。肝细胞癌组织中高水平的乙酰化甲胎蛋白与乙肝病毒感染相关，并与预后不良和患者生存期减少相关。在肝癌细胞中，乙肝病毒X蛋白(HBx)和棕榈酸(PA)通过破坏SIRT1介导的脱乙酰化而增加乙酰化AFP的水平。AFP乙酰化在肝细胞癌的进展中起着重要作用，为肝细胞癌提供了一个新的潜在的预后标志物和治疗靶点。
Alpha-fetoprotein (AFP) is a well-established biomarker for hepatocellular carcinoma (HCC). Here, we investigated the acetylation state of AFP in vivo. AFP acetylation was regulated by the acetyltransferase CBP and the deacetylase SIRT1. Acetylation of AFP at lysines 194, 211, and 242 increased the stability of AFP protein by decreasing its ubiquitination and proteasomal degradation. AFP acetylation promoted its oncogenic role by blocking binding to the phosphatase PTEN and the pro-apoptotic protein caspase-3, which increased signaling for proliferation, migration, and invasion and decreased apoptosis. High levels of acetylated AFP in HCC tissues were associated with HBV infection and correlated with poor prognosis and decreased patient survival. In HCC cells, hepatitis B virus X protein (HBx) and palmitic acid (PA) increased the level of acetylated AFP by disrupting SIRT1-mediated deacetylation. AFP acetylation plays an important role in HCC progression and provides a new potential prognostic marker and therapeutic target for HCC.