Abstract
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.
Highlights
Aberrant DNA methylation is the primary epigenetic mechanism for regulating gene expression in human cancers [1, 2]
Several studies have shown that lower global levels of H3K9me2 predict poor prognosis in prostate and kidney cancers [36, 37]
We analyzed the correlation between G9a and H3K9me2 level in human lung cancer tissue microarray (TMA)
Summary
Aberrant DNA methylation is the primary epigenetic mechanism for regulating gene expression in human cancers [1, 2]. Aberrant silencing of tumor suppressor genes DSC3 and MASPIN in breast epithelial tumor cells has been previously linked to DNA methylation and H3K9 dimethylation of their promoters [11]. It has been reported that changes in global levels of individual histone modifications are independently predictive of the clinical outcome of prostate cancer, gastric adenocarcinomas, as well as breast, ovarian, and pancreatic cancers [12,13,14]. These results support the hypothesis that aberrant histone modification patterns are critically involved in the tumorigenic process
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