Deletion of TMEM268 inhibits growth of gastric cancer cells by downregulating the ITGB4 signaling pathway

• Published in: Cell death and differentiation 2019-08, Vol.26 (8), p.1453-1466
• Main Authors: Hong, Dubeiqi, Zhang, Xuan, Li, Riyong, Yu, Jiahong, Lou, Yaxin, He, Qihua, Li, Xuanze, Xu, Dong, Lv, Ping, Lin, Jian, Chen, Yingyu
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 14; 14/1; 14/19; 14/28; 14/34; 38; 631/67/1244; 631/80/79/1236; 82/80; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell adhesion; Cell adhesion & migration; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell viability; Clonal deletion; Cytoskeleton; Gastric cancer; Homeostasis; Intravenous administration; Life Sciences; Metastases; Molecular modelling; Peritoneum; Proteins; Signal transduction; Stem Cells; Tumorigenesis; Ubiquitin; Xenografts
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-018-0223-3

Transmembrane protein 268 ( TMEM268 ) encodes a novel human protein of previously unknown function. This study analyzed the biological activities and molecular mechanisms of TMEM268 in vivo and in vitro. We found that TMEM268 deletion decreases cell viability, proliferation, and cell adhesion as well as causing S-phase cell cycle arrest and disrupts cytoskeleton remolding. Xenograft tumor mouse model studies showed that TMEM268 deletion inhibits the tumorigenesis of BGC823 gastric cancer cells. In addition, TMEM268- deleted BGC823 cells failed to colonize the lungs after intravenous injection and to form metastatic engraftment in the peritoneum. Molecular mechanism studies showed a C-terminal interaction between TMEM268 and integrin subunit β4 (ITGB4). TMEM268 knockout promotes ITGB4 ubiquitin-mediated degradation, increasing the instability of ITGB4 and filamin A (FLNA). The reduced ITGB4 protein levels result in the disassociation of the ITGB4/PLEC complex and cytoskeleton remodeling. This study for the first time demonstrates that TMEM268 plays a positive role in the regulation of ITGB4 homeostasis. The above results may provide a new perspective that targeting the TMEM268/ITGB4 signaling axis for the treatment of gastric cancer, which deserves further investigation in the future.