Ncor2 Regulates Glioblastoma Progression And Treatment Resistance

Glioblastoma Multiforme (GBM, WHO Grade IV glioma) is one of the deadliest adult CNS tumors with a median survival of less than two years. It is largely resistant to aggressive therapeutic regimes, which combine radiation, chemotherapy and surgery. Thus, it is imperative to identify the molecular players and pathways that facilitate GBM resistance and recurrence. Nuclear co-repressor protein NCoR2 is upregulated in GBM and its increased expression correlates with poor prognosis in GBM patients (Alrfaei. Plos one. 2013). NCoR2, through its binding to the histone deacetylase protein HDAC3, mediates transcriptional repression (Zhu et al. Brain Res. 2013). NCoR2 is also involved in maintenance of neural stem cells (Jepson et al. Nature. 2007), which contribute to treatment resistance. Our study employs two distinct lineages of glioma - the less aggressive proneural and the highly aggressive mesenchymal subtypes. We show that NCoR2 is differentially expressed across these subtypes, suggesting a role for NCoR2-mediated transcriptional reprogramming in GBM progression. Moreover, knockdown of NCoR2 leads to phenotypic changes both in vitro and in vivo - including effects on neurosphere formation and proliferation, differential expression of stem-like markers as well as regulation of tumor growth and progression in mice. We also demonstrate that NCoR2 expression is increased upon treatment with temozolomide (used for GBM therapy), indicating a protective pro-tumor role for NCoR2. Finally, we explore the contribution of the GBM microenvironment to GBM progression by varying the three-dimensional properties as well as the rigidity of the extracellular matrix and investigating changes in NCoR2 expression and its regulation of tumor progression. We conclude that NCoR2 regulates GBM progression and resistance to therapy potentially via inducing a stem-like phenotype as well as responding to the tumor-promoting mechanical cues within the GBM microenvironment. Citation Format: Shelly Kaushik, Joanna J. Phillips, Valerie M. Weaver. NCoR2 regulates glioblastoma progression and treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2017-3985