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.
Highlights
Glioma, the most common primary brain tumor of the adult central nervous system, is associated with a poor prognosis
We demonstrate that glyceryl triacetate (GTA) induces cytostatic growth arrest of primary tumor-derived oligodendroglioma cells that possess some features of OG cells more than established human oligodendroglioma cells (HOG and Hs683), but has little to no effect on normal cells (i.e., neural stem cells (NSCs) and a murine oligodendrocyte progenitor cells (OPCs) line, Oli-Neu)
To determine whether differences in GTA responsiveness were correlated with chromosomal alterations, all human cell lines used in this study were subjected to in-depth DNA analysis
Summary
The most common primary brain tumor of the adult central nervous system, is associated with a poor prognosis. Standard therapy of maximal surgical resection followed by concurrent radiotherapy and temozolomide (Temodar®) chemotherapy [1] has increased median survival for patients with glioblastoma (GBM, WHO grade IV astrocytoma) to ~14 months. Inasmuch as the median survival for patients with anaplastic oligodendroglioma without loss of heterozygosity (LOH) of 1p and 19q chromosome arms is comparable to that of GBM (i.e., 1.2 years) [3], studies focusing on novel oligodendroglioma therapeutic strategies are warranted. Tumor recurrence is nearly inevitable in high-grade glioma patients. Therapeutic approaches that selectively target these glioma stem cells (GSCs), while sparing normal neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs), the most abundant cycling population in the adult brain [5], are of considerable interest
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