Abstract
Epigenetic regulation of O6-alkylguanine DNA alkyltransferase (MGMT) is surrogate of intrinsic resistance to temozolomide (TMZ). However, mechanisms associated with adaptive resistance evolution of glioblastoma (GBM) relative to MGMT methylation remain unclear. We hereby report a paradoxical yet translational epigenetic regulation of plasticity towards adaptive resistance in GBM. Based on an adaptive resistance model of GBM cells with differential MGMT methylation profiles, MGMT-hypermethylation enhanced genetic and phenotypic plasticity towards adaptive resistance to TMZ while MGMT hypomethylation limited plasticity. The resulting model-associated adaptive resistance gene signature negatively correlated with GBM patient survival. XAF1, a tumor suppressor protein, paradoxically emerged as a mediator of differential plasticities towards adaptive resistance to TMZ through epigenetic regulation. XAF1 promoted resistance both in-vitro and in-vivo. Furthermore, XAF1 expression negatively correlated with XAF1 promoter methylation status, and negatively correlate with GBM patient survival. Collectively, XAF1 appears to have a pradoxical yet translational role in GBM.
Highlights
Cancer cells are highly evolved and adapted for survival despite therapeutic and adverse tumor microenvironmental challenges
We focused on genetic changes associated with evolution towards adaptive resistance through comparision of resistant cell lines with treatment-naïve cell lines
Even when TMZ is combined with radiotherapy following maximum-safe surgical resection, the median survival still remains dismal at 14 months secondary to adaptive resistance to therapy[8]
Summary
Cancer cells are highly evolved and adapted for survival despite therapeutic and adverse tumor microenvironmental challenges. Randomized clinical trials designed to target MGMT activity in GBM during TMZ treatment have not been very effective[11,12]. MGMT promoter methylation status is widely considered as a marker for intrinsic TMZ resistance, the role of epigenetic regulation of adaptive resistance in GBM remains unclear. We hereby report a paradoxical epigenetic regulation of plasticity towards adaptive resistance in GBM involving XIAP-associated factor 1 (XAF1). XAF1 a previously reported tumor suppressor[15,16,17], emerged as a key gene whose epigenetic regulation mediated differential plasticities towards adaptive resistance to TMZ in GBM. XAF1 a tumor suppressor protein, paradoxically emerged as a mediator of differential plasticities towards adaptive resistance to TMZ through epigenetic regulation. XAF1 appears to have a pradoxical role in GBM that is translational
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