Methyl-CpG targeted recruitment of p300 reactivates tumor suppressor genes in human cancer cells.
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 NFkappaB transcriptional activation domain (AD), accompanied by histone H3K9/K14 acetylation. Herein we demonstrate that p300 histone acetyltransferase (HAT), one of the NFkappaB (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.
Fukushige
Shinichi
S
Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Miyagi 980-8575, Japan. shinichi@mail.tains.tohoku.ac.jp
Kondo
Emiko
E
Horii
Akira
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D000070957:MutL Protein Homolog 1; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D050880:p300-CBP Transcription Factors; D000070957:MutL Protein Homolog 1