Distinct epigenetic regulation of tumor suppressor genes in putative cancer stem cells of solid tumors.
Epigenetic gene regulation plays essential roles in differentiation of embryonic and tissue stem cells. In these benign undifferentiated cells, some polycomb targeted genes are kept in a state of DNA hypomethylation and they have a distinct chromatin signature termed bivalent chromatin structure to maintain their plasticity. We hypothesized that cancer stem cells (CSC), the malignant counterpart of these cells, are also under the control of epigenetics like benign stem cells. We compared the DNA methylation and chromatin structure in 10 tumor suppressor genes between CSC and differentiated cancer cells of MCF7 and Huh7 cells. We found that the level of DNA methylation was indeed significantly lower in CSC, while surprisingly, the bivalent chromatin structure was more ubiquitously seen in differentiated cancer cells compared to CSC. However, repressive marks of chromatin structure, namely H3K27me3 and EZH2, were significantly lower in CSC. As a consequence, CSC remained in a higher transcriptionally active chromatin state compared to differentiated cancer cells. We found that the differentiation of CSCs is also epigenetically regulated. These findings could help towards a comprehensive understanding of CSC, and also improve the development of eradicative therapies against human malignancies.
Department of Pulmonary Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Hiroyuki
H
Yasuda
Kenzo
K
Soejima
Hideo
H
Watanabe
Ichiro
I
Kawada
Ichiro
I
Nakachi
Satoshi
S
Yoda
Sohei
S
Nakayama
Ryosuke
R
Satomi
Shinnosuke
S
Ikemura
Hideki
H
Terai
Takashi
T
Sato
Sadafumi
S
Suzuki
Yumi
Y
Matsuzaki
Katsuhiko
K
Naoki
Akitoshi
A
Ishizaka
D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2