Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways.

ABSTRACT: Glioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ER?), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ER? contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ER? in the DNA damage response of GBM cells, and tested whether ER? sensitizes GBM cells to chemotherapy. Cell viability and survival assays using multiple epitope tagged ER? expressing established and primary GBM cells demonstrated that ER? sensitizes GBM cells to DNA damaging agents including temozolomide (TMZ). RNA-seq studies using ER? overexpression models revealed downregulation of number of genes involved in DNA recombination and repair, ATM signaling and cell cycle check point control. Gene set enrichment analysis (GSEA) suggested that ER?-modulated genes were correlated negatively with homologous recombination, mismatch repair and G2M checkpoint genes. Further, RT-qPCR analysis revealed that chemotherapy induced activation of cell cycle arrest and apoptosis genes were attenuated in ER?KO cells. Additionally, ER? overexpressing cells had a higher number of ?H2AX foci following TMZ treatment. Mechanistic studies showed that ER? plays an important role in homologous recombination (HR) mediated repair and ER? reduced expression and activation of ATM upon DNA damage. More importantly, GBM cells expressing ER? had increased survival when compared to control GBM cells in orthotopic GBM models. ER? overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models. Additionally, IHC analysis revealed that ER? tumors had increased expression of ?H2AX and cleaved caspase-3. Using ER?-overexpression and ER?-KO GBM model cells, we have provided the evidence that ER? is required for optimal chemotherapy induced DNA damage response and apoptosis in GBM cells.

SUBMITTER: Zhou M 

PROVIDER: S-EPMC6467924 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature