H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM
Journal
Cancer Research
Journal Volume
70
Journal Issue
20
Pages
7830-7840
Date Issued
2010
Author(s)
Chen M.-W.
Kao H.-J.
Chi C.-C.
Johansson G.
Shiah S.-G.
Chen P.-S.
Lai T.-C.
Chang J.-S.
Jan Y.-H.
Chien M.-H.
Yang C.-J.
Huang M.-S.
Hsiao M.
Kuo M.-L.
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. ?2010 AACR.
SDGs
Other Subjects
DNA methyltransferase 1; epithelial cell adhesion molecule; heterochromatin protein 1; histone deacetylase 1; histone methyltransferase; animal experiment; animal model; animal tissue; article; cancer invasion; cell invasion; cell migration; controlled study; DNA methylation; epigenetics; female; human; human tissue; lung cancer; metastasis; metastasis inhibition; mouse; nonhuman; priority journal; prognosis; promoter region; protein expression; RNA interference; Adenocarcinoma; Animals; Antigens, Neoplasm; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Female; Gene Silencing; Genes, Reporter; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Humans; Luciferases; Lung Neoplasms; Lymphatic Metastasis; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Polymerase Chain Reaction; Prognosis; RNA, Neoplasm
Type
journal article