Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Cell Line, Tumor
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Cell Movement*
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E1A-Associated p300 Protein / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Histocompatibility Antigens / genetics
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Histocompatibility Antigens / metabolism*
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Humans
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Integrin beta3 / genetics
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Integrin beta3 / metabolism*
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Male
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Neoplasm Invasiveness
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PR-SET Domains
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Pancreatitis-Associated Proteins / metabolism
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Peritoneal Neoplasms / enzymology*
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Peritoneal Neoplasms / genetics
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Peritoneal Neoplasms / mortality
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Peritoneal Neoplasms / secondary
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Phosphorylation
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Promoter Regions, Genetic
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Receptors, Glucocorticoid / metabolism
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Signal Transduction
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Sp1 Transcription Factor / metabolism
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Stomach Neoplasms / enzymology*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / mortality
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Stomach Neoplasms / pathology
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Up-Regulation
Substances
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Biomarkers, Tumor
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Histocompatibility Antigens
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ITGB3 protein, human
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Integrin beta3
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Pancreatitis-Associated Proteins
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REG4 protein, human
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Receptors, Glucocorticoid
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Sp1 Transcription Factor
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SP1 protein, human
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EHMT2 protein, human
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Histone-Lysine N-Methyltransferase
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E1A-Associated p300 Protein
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EP300 protein, human
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Extracellular Signal-Regulated MAP Kinases