Histone deacetylase inhibitors enhance estrogen receptor beta expression and augment agonist-mediated tumor suppression in glioblastoma.
Neurooncol Adv
; 3(1): vdab099, 2021.
Article
en En
| MEDLINE
| ID: mdl-34485908
BACKGROUND: Glioblastomas (GBMs) are the most lethal primary brain tumors. Estrogen receptor ß (ESR2/ERß) function as a tumor suppressor in GBM, however, ERß expression is commonly suppressed during glioma progression. In this study, we examined whether drugs that reverse epigenetic modifications will enhance ERß expression and augment ERß 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 ERß in GBM cells. Treatment with HDACi uniquely upregulated ERß isoform 1 expression that functions as a tumor suppressor but not ERß isoform 5 that drives oncogenic functions. Further, combination therapy of HDACi with the ERß agonist, LY500307, potently reduced cell viability, invasion, colony formation, and enhanced apoptosis. Mechanistic studies showed that HDACi induced ERß is functional, as it enhanced ERß reporter activities and ERß target genes expression. ChIP analysis confirmed alterations in the histone acetylation at the ERß 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 ERß expression that commonly occurs in GBM progression.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Neurooncol Adv
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido