ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. (10th July 2020) - Xu, Qingfu
Abstract: Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133 + and SSEA-1 + cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics. Highlights: POLD2 is highly expressed in surgical glioma specimens and its expression correlates with poor patient survival. POLD2 expression promotes GBM malignancy. Inhibition of POLD2 expression sensitizes glioma cells to temozolomide and γ-radiation. POLD2 expression is enriched in GBM stem-like cells. POLD2-KD + γ-radiation cooperatively inhibit in vivo glioblastoma xenograft growth.