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Treatment-refractory glioma stem and tumor cells exhibit phenotypic plasticity driving recurrence, but the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide a trophic niche to promote proliferation of irradiated glioma cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation, and inhibits the phenotypic transition and tumor growth. Our findings highlight an important role for P300 histone acetyltransferase in treatment-induced plasticity and opens a new therapeutic avenue for preventing glioma recurrence.SignificanceOur study demonstrates that radiation therapy promotes glioma resistance by inducing vascular-like phenotypes in GSC that, in turn, aid in proliferation of the remaining tumor cells. This phenotype switch is mediated by P300 HAT, and inhibition of this enzyme is a potential therapeutic target for preventing glioma recurrence following radiation.

Author(s): Zhong, Amy; Chang, Melissa; Yu, Theresa; Gau, Raymond; Riley, Daniel J; Chen, Yumay; Chen, Phang-Lang | Abstract: BackgroundHigher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways.ResultsNormal renal epithelial cells and renal cell carcinoma cells are more chemo- and radiation resistant when cultured in high concentrations of glucose. In high glucose conditions, the CHK1-mediated DNA damage response is not activated properly. Cells in high glucose also have slower DNA repair rates and accumulate more mutations than cells grown in normal glucose concentrations. Ultimately, these cells develop a transforming phenotype.ConclusionsIn high glucose conditions, defective DNA damage responses most likely contribute to the higher mutation rate in renal epithelial cells, in addition to oxidative DNA damage. The DNA damage and repair are normal enzyme dependent mechanisms requiring euglycemic environments. Aberrant DNA damage response and repair in cells grown in high glucose conditions underscore the importance of maintaining good glycemic control in patients with diabetes mellitus and cancer.