EPIG-05RADIORESISTANCE OF PODOPLANIN-EXPRESSING GLIOMA STEM CELLS IS ASSOCIATED WITH EZH2-DRIVEN POLYCOMB REPRESSIVE COMPLEX ACTIVITY

Abstract

Glioblastoma (GBM) is the most frequently occurring malignant primary tumor of the central nervous system, and despite aggressive clinical intervention, GBM is uniformly fatal. Data from multiple expression profiling experiments suggest that the type-I integral membrane glycoprotein podoplanin (PDPN) is an important prognostic marker in astrocytic gliomas independent of a number of relevant clinical factors. We recently discovered that radiotherapy (RT) resistance of GBM is associated with global DNA hypermethylation and hypothesized that PDPN may be involved in this phenomenon. Indeed, we found that PDPN knockdown sensitized glioma sphere-forming cells (GSCs) to RT in vitro. Furthermore, upon profiling PDPN-sorted GSC subpopulations, enrichment analysis revealed that PDPN upregulates polycomb repressive complex (PRC) activity to promote EZH2-driven global DNA hypermethylation. EZH2 is known to directly control DNA methylation, and we have previously shown that EZH2 protects GSCs from radiation-induced cell death. This is the first report implicating PDPN in EZH2-mediated RT resistance, and we believe the membrane protein may be a meaningful therapeutic target in RT resistant GBM. In summary, PDPN is a novel prognostic marker for individuals with astrocytic gliomas and promotes EZH2-mediated RT resistance in GSCs.