TY - JOUR
T1 - Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells
AU - Fukushige, Shinichi
AU - Kondo, Emiko
AU - Horii, Akira
N1 - Funding Information:
We are grateful to Dr. Toshikazu Takeshita (Tohoku University School of Medicine) for providing 293T cell line, Takahiro Miura (Tohoku University School of Medicine) for technical assistance, Mami Mori (Tohoku University School of Medicine) for secretarial assistance, and Dr. B.L.S. Pierce (University of Maryland University College) for editorial work in the preparation of this manuscript. This work was supported by Grants-in-Aid (No. 18390117 to S.F., and Nos. 17015003 and 20012009 to A.H.), the 21st Century COE Program Special Research Grant (A.H.), and Academic Frontier Project for Private Universities: matching fund subsidy 2006–2010 (A.H.) from the Ministry of Education, Culture, Sports, Science and Technology, and by a Grant-in-Aid for Cancer Research, Ministry of Health, Labour and Welfare of Japan (No. 18–10 to A.H.).
PY - 2008/12/12
Y1 - 2008/12/12
N2 - DNA methylation and histone modifications are both major features of the epigenetic silencing seen at tumor suppressor genes (TSGs) in cancer. DNA methylation inhibitors, but not, in general, histone deacetylase, can reactivate TSGs. However, DNA methylation inhibitors frequently upregulate genes whose promoters remain unmethylated. Herein we demonstrated that the methyl-CpG targeted transcriptional activation (MeTA), which allows re-expression of TSGs without DNA demethylation, is widely seen in human cancer. We further analyzed MeTA and found that transcriptional coactivators are recruited at hypermethylated promoter regions of TSGs using the methyl-CpG binding domain (MBD). Reactivation of MLH1 by MeTA accompanied acetylation of histone H3 lysine 9/14 at the promoter region. Furthermore, all ten genes analyzed in three cell lines were reactivated by the effect of MeTA. Our present results lead to an efficient way to search for transcriptionally silenced genes with highly methylated CpG islands, particularly TSGs in cancer and developmentally important genes in embryonic stem cells.
AB - DNA methylation and histone modifications are both major features of the epigenetic silencing seen at tumor suppressor genes (TSGs) in cancer. DNA methylation inhibitors, but not, in general, histone deacetylase, can reactivate TSGs. However, DNA methylation inhibitors frequently upregulate genes whose promoters remain unmethylated. Herein we demonstrated that the methyl-CpG targeted transcriptional activation (MeTA), which allows re-expression of TSGs without DNA demethylation, is widely seen in human cancer. We further analyzed MeTA and found that transcriptional coactivators are recruited at hypermethylated promoter regions of TSGs using the methyl-CpG binding domain (MBD). Reactivation of MLH1 by MeTA accompanied acetylation of histone H3 lysine 9/14 at the promoter region. Furthermore, all ten genes analyzed in three cell lines were reactivated by the effect of MeTA. Our present results lead to an efficient way to search for transcriptionally silenced genes with highly methylated CpG islands, particularly TSGs in cancer and developmentally important genes in embryonic stem cells.
KW - CpG island
KW - Histone modifications
KW - JMJD2D
KW - MLH1
KW - MeTA
KW - Methyl-CpG binding domain
KW - NFκB transcriptional activation domain
KW - Transcriptional repression
KW - Tumor suppressor genes
UR - http://www.scopus.com/inward/record.url?scp=55549138008&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55549138008&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2008.10.016
DO - 10.1016/j.bbrc.2008.10.016
M3 - Article
C2 - 18929535
AN - SCOPUS:55549138008
VL - 377
SP - 600
EP - 605
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -
