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Abstract
Abstract Although, the epigenetic regulation of O6-alkylguanine DNA alkyltransferase (MGMT) in GBM is an established surrogate of intrinsic resistance to temozolomide (TMZ), the evolution of GBM habitats towards adaptive resistance to TMZ relative to MGMT promoter methylation status remains unclear. We report a novel epigenetic regulation of plasticity towards adaptive resistance in GBM. Using an adaptive TMZ resistance model of MGMT-hypermethylated and MGMT-hypomethylated GBM cellular habitats, a counter-intuitive inverse correlation was noted between intrinsic MGMT-dependent TMZ resistance versus plasticity towards adaptive TMZ resistance. Upon TMZ challenge, GBM cellular habitats with lower intrinsic resistance demonstrated significant genetic perturbations and aggressive phenotypic alterations compared to GBM habitats with higher intrinsic resistance. A resulting gene signature associated with plasticity for adaptive resistance from our model significantly correlated with GBM survival in the TCGA dataset. XAF-1 emerged as a key gene whose epigenetic regulation mediated differential plasticity towards adaptive resistance to TMZ in GBM habitats. Genetic silencing of XAF-1 significantly compromised plasticity towards adaptive resistance. XAF1 expression was found to highly correlate with promoter methylation status, and negatively correlate with long-term survival in GBM patient survival. Our studies have shed some light with respect to the plasticity of GBM habitats towards adaptive resistance evolution to TMZ relative to MGMT promoter methylation status. Particularly, a novel and translational role for XAF1 in GBM has been uncovered.
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