KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells
KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells
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DOI：
10.1016/j.canlet.2019.09.015
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Xing, Dongming
中科院分区：
文献类型：
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作者：
Tong, Yingying;Guo, Dong;Xing, Dongming
频繁发生的组蛋白赖氨酸琥珀酰化是一种新发现的组蛋白修饰，可由 KAT2A 组蛋白琥珀酰转移酶（也是一种组蛋白乙酰转移酶）调节。 KAT2A 组蛋白琥珀酰转移酶活性对于肿瘤发生很重要；然而，这种促肿瘤作用的机制仍然难以捉摸。在这里，我们证明 KAT2A 在人胰腺导管腺癌 (PDAC) 标本中高表达，并且与 PDAC 的晚期阶段和患者的较短生存期呈正相关。此外，PDAC标本中的KAT2A表达与14-3-3 zeta表达相关，并且KAT2A调节YWHAZ启动子区域的H3K79琥珀酰化（编码14-3.3 zeta以促进YWHAZ mRNA和14-3-3 zeta表达，从而防止β-连环蛋白降解。琥珀酰转移酶活性缺陷的KAT2A Y645A的表达降低H3K79 琥珀酰化和 14-3-3 zeta 表达，导致 β-catenin 稳定性降低，随后细胞周期蛋白 D1、c-Myc、GLUT1 和 LDHA 的表达降低，KAT2A 介导的 14.3-3 zeta 和 β-catenin 表达促进 PDAC 细胞的糖酵解、细胞增殖以及上皮间质转化的迁移和侵袭。 KAT2A 介导的组蛋白琥珀酰化调节基因表达和 β-连环蛋白稳定性，促进肿瘤细胞增殖和侵袭。
Frequently occurring histone lysine succinylation is a newly identified histone modification that can be regulated by KAT2A histone succinyltransferase, which is also a histone acetyltransferase. KAT2A histone succinyl-transferase activity is important for tumorigenesis; however, the mechanism underlying this tumor-promoting effect remains elusive. Here we demonstrate that KAT2A is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens and positively correlated with advanced stages of PDAC and short patients' survival. In addition, KAT2A expression in PDAC specimens is correlated with 14-3-3 zeta expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3.3 zeta to promote YWHAZ mRNA and 14-3-3 zeta expression, thereby preventing beta-catenin degradation. Expression of succinyltransferase activity-defective KAT2A Y645A reduces H3K79 succinylation and 14-3-3 zeta expression, leading to decreased beta-catenin stability and subsequently decreased expression of cyclin D1, c-Myc, GLUT1, and LDHA. KAT2A-mediated 14.3-3 zeta and beta-catenin expression promotes glycolysis, cell proliferation, and migration and invasion of PDAC cells with epithelial-to-mesenchymal transition. These findings reveal a novel and instrumental role of KAT2A-mediated histone succinylation in regulation of gene expression and beta-catenin stability to promote tumor cell proliferation and invasion.