Open AccessSuccinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression
Author(s) -
Wang Xingyun,
Shi Xiao,
Lu Hongcheng,
Zhang Chen,
Li Xiang,
Zhang Tiancheng,
Shen Jiajia,
Wen Jianfei
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202200546
Subject(s) - succinylation , fibrillin , chemistry , extracellular matrix , matrix metalloproteinase , microbiology and biotechnology , tumor progression , biochemistry , biology , acetylation , gene
Extracellular matrix (ECM) remodeling is crucial in the regulation of gastric cancer (GC) progression. This work aims to reveal novel posttranslational modifications and their relevant mechanisms in GC. In 3D matrix culture and animal models, it is found that fibrillin 1 (FBN1) expression is increased in advanced GC and has succinylation modification. The succinylation modification of FBN1 blocks its degradation by matrix metalloproteinases (MMPs). The long‐term accumulation and deposition of FBN1 enhance tumor progression by activating TGF‐ β 1 and intracellular PI3K/Akt pathway. The FBN1 succinylation site monoclonal antibody can effectively intervene the effect of succinylation modification and inhibit GC progression. FBN1 is specifically upregulated in the progression of GC compared with other tumors. In conclusion, FBN1 is widely present in the form of K672‐succinylated modifications in GC. Besides, the succinyl group of FBN1 blocks its binding to MMP2, inhibits its degradation by MMP2, and leads to the accumulation of FBN1, which poses a long‐term risk to the poor prognosis of GC.