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KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells.

Authors
  • Tong, Yingying1
  • Guo, Dong2
  • Yan, Dong3
  • Ma, Chunmin4
  • Shao, Fei5
  • Wang, Yugang6
  • Luo, Shudi2
  • Lin, Liming2
  • Tao, Jingjing2
  • Jiang, Yuhui4
  • Lu, Zhimin7
  • Xing, Dongming8
  • 1 The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China; Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China. , (China)
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310029, China. , (China)
  • 3 Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China. , (China)
  • 4 The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. , (China)
  • 5 Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266071, China; Qingdao Cancer Institute, Qingdao, Shandong, 266071, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. , (China)
  • 6 Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. , (China)
  • 7 The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310029, China. Electronic address: [email protected] , (China)
  • 8 Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266071, China; Qingdao Cancer Institute, Qingdao, Shandong, 266071, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Cancer letters
Publication Date
Oct 11, 2019
Volume
469
Pages
1–10
Identifiers
DOI: 10.1016/j.canlet.2019.09.015
PMID: 31610265
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 succinyltransferase 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 14-3-3ζ expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3-3ζ) to promote YWHAZ mRNA and 14-3-3ζ expression, thereby preventing β-catenin degradation. Expression of succinyltransferase activity-defective KAT2A Y645A reduces H3K79 succinylation and 14-3-3ζ expression, leading to decreased β-catenin stability and subsequently decreased expression of cyclin D1, c-Myc, GLUT1, and LDHA. KAT2A-mediated 14-3-3ζ and β-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 β-catenin stability to promote tumor cell proliferation and invasion. Copyright © 2019 Elsevier B.V. All rights reserved.

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