ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics

Qingfu Xu, Chengchen Hu, Yan Zhu, Kimberly Wang, Bachuchu Lal, Lichao Li, Junhai Tang, Shuang Wei, Guohao Huang, Shuli Xia, Shengqing Lv, John Laterra, Yugang Jiang, Yunqing Li

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)126-135
Number of pages10
JournalCancer Letters
Volume482
DOIs
StatePublished - Jul 10 2020

Keywords

  • Chemo-/radiation
  • Cytoprotective oncogene
  • GBM stem-like cells
  • POLD2
  • Sensitizer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Xu, Q., Hu, C., Zhu, Y., Wang, K., Lal, B., Li, L., Tang, J., Wei, S., Huang, G., Xia, S., Lv, S., Laterra, J., Jiang, Y., & Li, Y. (2020). ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. Cancer Letters, 482, 126-135. https://doi.org/10.1016/j.canlet.2020.01.011