Canine glioma stem-like cells demonstrate DNA methylation-dependent enhancement of cellular respiration following low oxygen tension

Abstract

Glioma stem cells (GSCs) have been implicated in radio- and chemotherapeutic resistance of glioblastoma (GBM). Therapeutic targeting of GSCs has shown promise in immunocompromised rodent models but have not been translated into effective therapies for human patients. The limited success of translating therapies from rodent models to GBM patients may be attributed, in part, to the lack of co-evolution between tumors and the tumor microenvironment in immunocompromised rodent models. Thus, spontaneous canine high-grade gliomas (HGGs) may provide a complementary translational model for human therapeutic development. While described in canine HGGs, little is known about canine glioma stem cell biology. In this study, we evaluatedcellular metabolism, DNA methylation, gene expression, and functional tests of malignancy to interrogate differences between canine glioma stem-cell like (GSLC) lines and a traditional serum grown glioma cell line following exposure to hypoxia. Hypoxia increased oxygen consumption rates in GSLCs, which correlated with hypoxia-induced hypomethylation and increased mRNA levels of genes important in cellular metabolism and stemness (e.g., KCNN3, KDM4B, TCF7L2), as well as augmented features of malignancy in GSLCs. Importantly, we were able to demonstrate a positive correlation between up-regulated genes in human GBM GSCs and hypomethylation of orthologous canine genes following hypoxia. Together, these data highlight similarities between canine and human GBM GSC cellular metabolism and their epigenetic regulation.