Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer
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(2020) 39:172
RESEARCH
Open Access
Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer Xiang Li1,2,3†, Chen Zhang2†, Ting Zhao1†, Zhongping Su2, Mengjing Li2, Jiancheng Hu4,5, Jianfei Wen6, Jiajia Shen6, Chao Wang2, Jinshun Pan2, Xianmin Mu2, Tao Ling2, Yingchang Li1, Hao Wen2, Xiaoren Zhang1,7 and Qiang You1,2,7*
Abstract Background: Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored. Methods: Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments. Results: Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration. Conclusions: Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC. Keywords: Lysine succinylation, Gastric cancer, LDHA, SQSTM1, CPT1A
* Correspondence: [email protected] † Xiang Li, Chen Zhang and Ting Zhao contributed equally to this work. 1 Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China 2 Department of Biotherapy, Department of Surgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
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