Succinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2022 Jul 28

PMID 35901491

Authors

Xingyun Wang

Xiao Shi

Hongcheng Lu

Chen Zhang

Xiang Li

Tiancheng Zhang

Jiajia Shen

Jianfei Wen

Affiliations

Soon will be listed here.

Abstract

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-β1 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.

Citing Articles

Unlocking the Hidden Potential of Cancer Therapy Targeting Lysine Succinylation.

Zheng Z, Xiao P, Kuang J, Wang Z, Wang X, Huang D J Cancer. 2025; 16(3):821-834.

PMID: 39781339 PMC: 11705062. DOI: 10.7150/jca.105849.

Mechanistic insights into SIRT7 and EZH2 regulation of cisplatin resistance in bladder cancer cells.

Cao Y, Wang S, Ma J, Long M, Ma X, Yang X Cell Death Dis. 2024; 15(12):931.

PMID: 39719443 PMC: 11668892. DOI: 10.1038/s41419-024-07321-1.

SIRT5 participates in the suppressive tumor immune microenvironment of EGFR-mutant LUAD by regulating the succinylation of ACAT1.

Shouhan W, Qingchang L, Xiaodan S Heliyon. 2024; 10(21):e39743.

PMID: 39524872 PMC: 11543872. DOI: 10.1016/j.heliyon.2024.e39743.

Phenotypic Heterogeneity of Patients With Marfan Syndrome in Puerto Rico: A Case Series.

Jimenez-Berrios G, Vazquez-Folch S, Izquierdo N Cureus. 2024; 16(9):e68791.

PMID: 39376868 PMC: 11456412. DOI: 10.7759/cureus.68791.

Huangqi-Danshen Decoction Against Renal Fibrosis in UUO Mice via TGF-β1 Induced Downstream Signaling Pathway.

Huang X, Peng Y, Lu L, Gao L, Wu S, Lu J Drug Des Devel Ther. 2024; 18:4119-4134.

PMID: 39296670 PMC: 11410030. DOI: 10.2147/DDDT.S457100.

References

Boyd N, Martin L, Yaffe M, Minkin S . Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res. 2011; 13(6):223. PMC: 3326547. DOI: 10.1186/bcr2942. View

Oudin M, Jonas O, Kosciuk T, Broye L, Guido B, Wyckoff J . Tumor Cell-Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression. Cancer Discov. 2016; 6(5):516-31. PMC: 4854754. DOI: 10.1158/2159-8290.CD-15-1183. View

Jain R . Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013; 31(17):2205-18. PMC: 3731977. DOI: 10.1200/JCO.2012.46.3653. View

Marigo I, Trovato R, Hofer F, Ingangi V, Desantis G, Leone K . Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages. Cancer Discov. 2020; 10(11):1758-1773. DOI: 10.1158/2159-8290.CD-20-0036. View

Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y . Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2010; 7(1):58-63. PMC: 3065206. DOI: 10.1038/nchembio.495. View

Wang C, Zhang C, Li X, Shen J, Xu Y, Shi H . CPT1A-mediated succinylation of S100A10 increases human gastric cancer invasion. J Cell Mol Med. 2018; 23(1):293-305. PMC: 6307794. DOI: 10.1111/jcmm.13920. View

Hubmacher D, El-Hallous E, Nelea V, Kaartinen M, Lee E, Reinhardt D . Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly. Proc Natl Acad Sci U S A. 2008; 105(18):6548-53. PMC: 2373353. DOI: 10.1073/pnas.0706335105. View

Benton G, Arnaoutova I, George J, Kleinman H, Koblinski J . Matrigel: from discovery and ECM mimicry to assays and models for cancer research. Adv Drug Deliv Rev. 2014; 79-80:3-18. DOI: 10.1016/j.addr.2014.06.005. View

Salvo E, Garasa S, Dotor J, Morales X, Pelaez R, Altevogt P . Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer. Mol Cancer. 2014; 13:112. PMC: 4049383. DOI: 10.1186/1476-4598-13-112. View

10.

Choudhary C, Weinert B, Nishida Y, Verdin E, Mann M . The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014; 15(8):536-50. DOI: 10.1038/nrm3841. View

11.

Sui H, Zhao J, Zhou L, Wen H, Deng W, Li C . Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett. 2017; 403:86-97. DOI: 10.1016/j.canlet.2017.05.013. View

12.

Wen J, Wang Y, Gao C, Zhang G, You Q, Zhang W . Helicobacter pylori infection promotes Aquaporin 3 expression via the ROS-HIF-1α-AQP3-ROS loop in stomach mucosa: a potential novel mechanism for cancer pathogenesis. Oncogene. 2018; 37(26):3549-3561. DOI: 10.1038/s41388-018-0208-1. View

13.

Zhao Z, Wang Y, Chu Y, Ye Z, Tao H . SPARC is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 2009; 16(1):260-8. DOI: 10.1158/1078-0432.CCR-09-1247. View

14.

Liu W, Huang K, Lu M, Huang H, Chen C, Cheng Y . TGF-β upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability. Oncogene. 2016; 36(19):2715-2723. PMC: 5442427. DOI: 10.1038/onc.2016.424. View

15.

Yang Z, Qi Y, Lai N, Zhang J, Chen Z, Liu M . Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1. J Exp Clin Cancer Res. 2018; 37(1):1. PMC: 5755139. DOI: 10.1186/s13046-017-0664-4. View

16.

Lee J, Wang M, Sudhir P, Chen G, Chi C, Chen J . Osteopontin promotes integrin activation through outside-in and inside-out mechanisms: OPN-CD44V interaction enhances survival in gastrointestinal cancer cells. Cancer Res. 2007; 67(5):2089-97. DOI: 10.1158/0008-5472.CAN-06-3625. View

17.

Wu J, Zhai J, Li C, Tan A, Wei P, Shen L . Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer. J Exp Clin Cancer Res. 2017; 36(1):160. PMC: 5688753. DOI: 10.1186/s13046-017-0631-0. View

18.

Bertero T, Oldham W, Grasset E, Bourget I, Boulter E, Pisano S . Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy. Cell Metab. 2018; 29(1):124-140.e10. PMC: 6432652. DOI: 10.1016/j.cmet.2018.09.012. View

19.

Chen Q, Zhang J, Ge W, Chen L, Yuan H, Meng L . YY1 inhibits the migration and invasion of pancreatic ductal adenocarcinoma by downregulating the FER/STAT3/MMP2 signaling pathway. Cancer Lett. 2019; 463:37-49. DOI: 10.1016/j.canlet.2019.07.019. View

20.

Jiang L, Zhang J, Monticone R, Telljohann R, Wu J, Wang M . Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis. Hypertension. 2012; 60(5):1192-9. PMC: 3487400. DOI: 10.1161/HYPERTENSIONAHA.112.196840. View