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Histone methyltransferase G9a and H3K9 dimethylation inhibit the self-renewal of glioma cancer stem cells.

Abstract
Epigenetic modification is crucial to keep the self-renewal and the "stemness" states of stem cells, not letting them to differentiate. The actual roles of Histone 3 Lysine 9 dimethylation (H3K9me2) and its methyltransferase G9a in this process are still unclear, especially in cancer stem cells. In our study, we found an interesting observation that most CD133-positive cells were H3K9me2 negative, both in glioma tissues and in cultured cells, although most cancer cells were detected to be H3K9me2 immunopositive. This implied that the G9a-dependent H3K9me2 was one of the crucial barriers of cancer stem cell self-renewal. To test the hypothesis, we examined the loss-of-function and gain-of-function of G9a. We found that bix01294, the selective inhibitor of G9a, can stimulate the sphere formation rate of glioma cancer stem cells, together with increasing Sox2 and CD133 expressions. The increase of CD133-active stem cells was confirmed by flow cytometry. On the other aspect, overexpression of G9a increased the H3K9me2 and decreased the sphere formation rate as well as the CD133 and Sox2 expressions. Since H3K9me2 modification is the major repressive switch, we predict that the repressive H3K9me2 modification may happen at the CD133 promoter regions. By chromatin precipitation assay, we confirmed that the CD133 and Sox2 promoter regions were modified by the H3K9me2. Therefore, we concluded that the G9a-dependent H3K9me2 repression on CD133 and Sox2 was one of the main switches of the self-renewal in glioma cancer stem cells.
AuthorsHong Tao, Haiying Li, Yanhuang Su, Danni Feng, Xilong Wang, Chun Zhang, Hui Ma, Qikuan Hu
JournalMolecular and cellular biochemistry (Mol Cell Biochem) Vol. 394 Issue 1-2 Pg. 23-30 (Sep 2014) ISSN: 1573-4919 [Electronic] Netherlands
PMID24833465 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • AC133 Antigen
  • Antigens, CD
  • Azepines
  • BIX 01294
  • Enzyme Inhibitors
  • Glycoproteins
  • Histocompatibility Antigens
  • Histones
  • PROM1 protein, human
  • Peptides
  • Quinazolines
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Lysine
Topics
  • AC133 Antigen
  • Antigens, CD (genetics, metabolism)
  • Azepines (pharmacology)
  • Brain Neoplasms (enzymology, genetics, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression Regulation, Neoplastic
  • Glioma (enzymology, genetics, pathology)
  • Glycoproteins (genetics, metabolism)
  • Histocompatibility Antigens (genetics, metabolism)
  • Histone-Lysine N-Methyltransferase (antagonists & inhibitors, genetics, metabolism)
  • Histones (metabolism)
  • Humans
  • Lysine
  • Methylation
  • Neoplastic Stem Cells (drug effects, enzymology, pathology)
  • Peptides (genetics, metabolism)
  • Promoter Regions, Genetic
  • Quinazolines (pharmacology)
  • SOXB1 Transcription Factors (genetics, metabolism)
  • Signal Transduction
  • Transfection

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