G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner

• Published in: Cell death & disease Vol. 9; no. 3; pp. 278 - 14
• Main Authors: Hu, Lei, Zang, Ming-de, Wang, He-xiao, Zhang, Bao-gui, Wang, Zhen-qiang, Fan, Zhi-yuan, Wu, Huo, Li, Jian-fang, Su, Li-ping, Yan, Min, Zhu, Zhi-qiang, Yang, Qiu-meng, Huang, Qiang, Liu, Bing-ya, Zhu, Zheng-gang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2018; Springer Nature B.V
• Subjects: 13/89; 96/1; Animals; Antibodies; Binding Sites; Biochemistry; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement; Dexamethasone; E1A-Associated p300 Protein - metabolism; Event-related potentials; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens - genetics; Histocompatibility Antigens - metabolism; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Immunology; Integrin beta3 - genetics; Integrin beta3 - metabolism; Life Sciences; Male; Medical prognosis; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Pancreatitis-Associated Proteins - metabolism; Peritoneal Neoplasms - enzymology; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - mortality; Peritoneal Neoplasms - secondary; Phosphorylation; PR-SET Domains; Promoter Regions, Genetic; Receptors, Glucocorticoid - metabolism; Signal Transduction; Sp1 Transcription Factor - metabolism; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Transcription; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0322-6

Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.