Acetate supplementation induces growth arrest of NG2/PDGFRα-positive oligodendroglioma-derived tumor-initiating cells.

Abstract

Cancer is associated with globally hypoacetylated chromatin and considerable attention has recently been focused on epigenetic therapies. N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate and ultimately acetyl-Coenzyme A for histone acetylation, are reduced in oligodendroglioma. The short chain triglyceride glyceryl triacetate (GTA), which increases histone acetylation and inhibits histone deacetylase expression, has been safely used for acetate supplementation in Canavan disease, a leukodystrophy due to ASPA mutation. We demonstrate that GTA induces cytostatic G0 growth arrest of oligodendroglioma-derived cells in vitro, without affecting normal cells. Sodium acetate, at doses comparable to that generated by complete GTA catalysis, but not glycerol also promoted growth arrest, whereas long chain triglycerides promoted cell growth. To begin to elucidate its mechanism of action, the effects of GTA on ASPA and acetyl-CoA synthetase protein levels and differentiation of established human oligodendroglioma cells (HOG and Hs683) and primary tumor-derived oligodendroglioma cells that exhibit some features of cancer stem cells (grade II OG33 and grade III OG35) relative to an oligodendrocyte progenitor line (Oli-Neu) were examined. The nuclear localization of ASPA and acetyl-CoA synthetase-1 in untreated cells was regulated during the cell cycle. GTA-mediated growth arrest was not associated with apoptosis or differentiation, but increased expression of acetylated proteins. Thus, GTA-mediated acetate supplementation may provide a safe, novel epigenetic therapy to reduce the growth of oligodendroglioma cells without affecting normal neural stem or oligodendrocyte progenitor cell proliferation or differentiation.

• Authors: Patrick M Long, Scott W Tighe, Heather E Driscoll, John R Moffett, Aryan M A Namboodiri, Mariano S Viapiano, Sean E Lawler, Diane M Jaworski
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e80714 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24278309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Antigens
• Proteoglycans
• chondroitin sulfate proteoglycan 4
• Receptor, Platelet-Derived Growth Factor alpha
• Amidohydrolases
• aspartoacylase

Topics

• Acetates (pharmacology)
• Acetylation (drug effects)
• Amidohydrolases (metabolism)
• Antigens (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Humans
• Mesoderm (drug effects, pathology)
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Oligodendroglioma (enzymology, pathology)
• Phenotype
• Protein Transport (drug effects)
• Proteoglycans (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (metabolism)