Novel Function of Lysine Methyltransferase G9a in the Regulation of Sox2 Protein Stability.
G9a is a lysine methyltransferase (KMTase) for histone H3 lysine 9 that plays critical roles in a number of biological processes. Emerging evidence suggests that aberrant expression of G9a contributes to tumor metastasis and maintenance of a malignant phenotype in cancer by inducing epigenetic silencing of tumor suppressor genes. Here, we show that G9a regulates Sox2 protein stability in breast cancer cells. When G9a lysine methyltransferase activity was chemically inhibited in the ER(+) breast cancer cell line MCF7, Sox2 protein levels were decreased. In addition, ectopic overexpression of G9a induced accumulation of Sox2. Changes in cell migration, invasion, and mammosphere formation by MCF7 cells were correlated with the activity or expression level of G9a. Ectopic expression of G9a also increased Sox2 protein levels in another ER(+) breast cancer cell line, ZR-75-1, whereas it did not affect Sox2 expression in MDA-MB-231 cells, an ER(-) breast cancer cell line, or in glioblastoma cell lines. Furthermore, treatment of mouse embryonic stem cells with a KMT inhibitor, BIX-01294, resulted in a rapid reduction in Sox2 protein expression despite increased Sox2 transcript levels. This finding suggests that G9a has a novel function in the regulation of Sox2 protein stability in a cell type-dependent manner.
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Jae-Young
JY
Lee
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Se-Hwan
SH
Lee
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Sun-Hee
SH
Heo
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Kwang-Soo
KS
Kim
Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Korea.
Changhoon
C
Kim
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Dae-Kwan
DK
Kim
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Jeong-Jae
JJ
Ko
Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
Kyung-Soon
KS
Park
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D006649:Histocompatibility Antigens; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase