Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer
| العنوان: | Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer |
|---|---|
| المؤلفون: | Jiajia Shen, Jianfei Wen, Xianmin Mu, Xiaoren Zhang, Hao Wen, Xiang Li, Chao Wang, Ting Zhao, Tao Ling, Zhongping Su, Qiang You, Jiancheng Hu, Jinshun Pan, Yingchang Li, Mengjing Li, Chen Zhang |
| المصدر: | Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 39, Iss 1, Pp 1-17 (2020) |
| بيانات النشر: | BioMed Central, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Cancer Research, Lung Neoplasms, Lysine, Succinic Acid, Apoptosis, Proximity ligation assay, CPT1A, Succinylation, Mice, 0302 clinical medicine, Ubiquitin, Sequestosome-1 Protein, Tumor Cells, Cultured, SQSTM1, Melanoma, education.field_of_study, biology, Chemistry, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Warburg effect, Gene Expression Regulation, Neoplastic, Survival Rate, Oncology, Biochemistry, 030220 oncology & carcinogenesis, Female, Lactate dehydrogenase A, Mice, Nude, lcsh:RC254-282, Gene Expression Regulation, Enzymologic, LDHA, 03 medical and health sciences, Sequestosome 1, Downregulation and upregulation, Stomach Neoplasms, Biomarkers, Tumor, Animals, Humans, education, Cell Proliferation, Lysine succinylation, Carnitine O-Palmitoyltransferase, L-Lactate Dehydrogenase, organic chemicals, Research, Xenograft Model Antitumor Assays, 030104 developmental biology, Proteolysis, biology.protein, bacteria, Gastric cancer, Lysosomes, Protein Processing, Post-Translational |
| الوصف: | 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 K222-succinylated 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. |
| اللغة: | English |
| تدمد: | 1756-9966 0392-9078 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9fe8ee5819b4ed7365a110be8cd83a52Test http://europepmc.org/articles/PMC7455916Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9fe8ee5819b4ed7365a110be8cd83a52 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17569966 03929078 |
|---|