H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM.

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.

• Authors: Min-Wei Chen, Kuo-Tai Hua, Hsin-Jung Kao, Chia-Chun Chi, Lin-Hung Wei, Gunnar Johansson, Shine-Gwo Shiah, Pai-Sheng Chen, Yung-Ming Jeng, Tsu-Yao Cheng, Tsung-Ching Lai, Jeng-Shou Chang, Yi-Hua Jan, Ming-Hsien Chien, Chih-Jen Yang, Ming-Shyan Huang, Michael Hsiao, Min-Liang Kuo
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 20 Pg. 7830-40 (Oct 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20940408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antigens, Neoplasm
• Cell Adhesion Molecules
• EPCAM protein, human
• Epithelial Cell Adhesion Molecule
• Histocompatibility Antigens
• RNA, Neoplasm
• Luciferases
• EHMT2 protein, human
• G9a protein, mouse
• Histone-Lysine N-Methyltransferase

Topics

• Adenocarcinoma (genetics, pathology)
• Animals
• Antigens, Neoplasm (genetics)
• Cell Adhesion Molecules (genetics)
• Cell Line, Tumor
• Cell Movement
• Epithelial Cell Adhesion Molecule
• Female
• Gene Silencing
• Genes, Reporter
• Histocompatibility Antigens (genetics, metabolism)
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Luciferases (genetics)
• Lung Neoplasms (genetics, pathology)
• Lymphatic Metastasis
• Mice
• Mice, SCID
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Polymerase Chain Reaction
• Prognosis
• RNA, Neoplasm (genetics)