Cancer esearch cular and Cellular Pathobiology 9 Histone Methyltransferase G 9 a Promotes Lung Cancer sion and Metastasis by Silencing the Cell R esion Molecule

nloaded is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppreses. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of nction in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in sive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockof G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis . Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metasechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary ancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for hylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the tment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings recrui establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression. Cancer Res; 70(20); 7830–40. ©2010 AACR.