TY - JOUR
T1 - Methyl-CpG targeted recruitment of p300 reactivates 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 the 293T cell line 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.), and The 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 - 2009/2/20
Y1 - 2009/2/20
N2 - Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor suppressor genes (TSGs) in cancer. We have previously shown that the methyl-CpG targeted transcriptional activation (MeTA) that allows re-expression of TSGs in human cancer cells is accomplished by combining a methyl-CpG binding domain (MBD) with a NFκB transcriptional activation domain (AD), accompanied by histone H3K9/K14 acetylation. Herein we demonstrate that p300 histone acetyltransferase (HAT), one of the NFκB (AD)-associated coactivators, reactivates epigenetically silenced MLH1 in 293T cells. Interestingly, the HAT domain of p300 is not essential for the reactivation of MLH1; instead, the C-terminal transactivation domain (C-TAD) but not the N-terminal one (N-TAD) reactivates MLH1. Furthermore, all ten of the cancer-related genes analyzed in three types of cancer cells were reactivated by the effect of p300 linked to MBD. These results demonstrate that it is possible to reactivate epigenetically silenced TSGs in human cancer cells by direct targeting of a transcriptional coactivator at highly methylated promoters.
AB - Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor suppressor genes (TSGs) in cancer. We have previously shown that the methyl-CpG targeted transcriptional activation (MeTA) that allows re-expression of TSGs in human cancer cells is accomplished by combining a methyl-CpG binding domain (MBD) with a NFκB transcriptional activation domain (AD), accompanied by histone H3K9/K14 acetylation. Herein we demonstrate that p300 histone acetyltransferase (HAT), one of the NFκB (AD)-associated coactivators, reactivates epigenetically silenced MLH1 in 293T cells. Interestingly, the HAT domain of p300 is not essential for the reactivation of MLH1; instead, the C-terminal transactivation domain (C-TAD) but not the N-terminal one (N-TAD) reactivates MLH1. Furthermore, all ten of the cancer-related genes analyzed in three types of cancer cells were reactivated by the effect of p300 linked to MBD. These results demonstrate that it is possible to reactivate epigenetically silenced TSGs in human cancer cells by direct targeting of a transcriptional coactivator at highly methylated promoters.
KW - CpG island
KW - Histone modification
KW - MBD
KW - MeTA
KW - NFκB
KW - Transcriptional activation domain
KW - Transcriptional repression
KW - Tumor suppressor gene
KW - p300
UR - http://www.scopus.com/inward/record.url?scp=58949096479&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58949096479&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2009.01.010
DO - 10.1016/j.bbrc.2009.01.010
M3 - Article
C2 - 19146826
AN - SCOPUS:58949096479
VL - 379
SP - 1021
EP - 1026
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -
