Histone deacetylase inhibitors enhance estrogen receptor beta expression and augment agonist-mediated tumor suppression in glioblastoma

Uday P. Pratap, Gangadhara R Sareddy, Zexuan Liu, Prabhakar Pitta Venkata, Junhao Liu, Weiwei Tang, Kristin A. Altwegg, Behnam Ebrahimi, Xiaonan Li, Rajeshwar R. Tekmal, Suryavathi Viswanadhapalli, Stanton McHardy, Andrew Brenner, Ratna K. Vadlamudi

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Glioblastomas (GBMs) are the most lethal primary brain tumors. Estrogen receptor β (ESR2/ERβ) function as a tumor suppressor in GBM, however, ERβ expression is commonly suppressed during glioma progression. In this study, we examined whether drugs that reverse epigenetic modifications will enhance ERβ expression and augment ERβ agonist-mediated tumor suppression. Methods: We tested the utility of epigenetic drugs which act as an inhibitor of histone deacetylases (HDACs), histone methylases, and BET enzymes. Mechanistic studies utilized RT-qPCR, chromatin immunoprecipitation (ChIP), and western blotting. Cell viability, apoptosis, colony formation, and invasion were measured using in vitro assays. An orthotopic GBM model was used to test the efficacy of in vivo. Results: Of all inhibitors tested, HDACi (panobinostat and romidepsin) showed the potential to increase the expression of ERβ in GBM cells. Treatment with HDACi uniquely upregulated ERβ isoform 1 expression that functions as a tumor suppressor but not ERβ isoform 5 that drives oncogenic functions. Further, combination therapy of HDACi with the ERβ agonist, LY500307, potently reduced cell viability, invasion, colony formation, and enhanced apoptosis. Mechanistic studies showed that HDACi induced ERβ is functional, as it enhanced ERβ reporter activities and ERβ target genes expression. ChIP analysis confirmed alterations in the histone acetylation at the ERβ and its target gene promoters. In orthotopic GBM model, combination therapy of panobinostat and LY500307 enhanced survival of tumor-bearing mice. Conclusions: Our results suggest that the combination therapy of HDACi and LY500307 provides therapeutic utility in overcoming the suppression of ERβ expression that commonly occurs in GBM progression.

Original languageEnglish (US)
Article numbervdab099
JournalNeuro-Oncology Advances
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Epigenetic drugs
  • estrogen receptor β
  • glioblastoma
  • panobinostat
  • romidepsin

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery

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