Histone deacetylase inhibitors enhance estrogen receptor beta expression and augment agonist-mediated tumor suppression in glioblastoma
Uday P Pratap1, Gangadhara R Sareddy1,2, Zexuan Liu1,3
1Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas, USA.
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.
Insights
Epigenetic drugs, specifically HDAC inhibitors, can restore tumor-suppressing Estrogen Receptor Beta (ERβ) expression in glioblastoma. Combining these drugs with an ERβ agonist improves glioblastoma treatment efficacy and patient survival.
Area of Science:
- Neuro-oncology
- Epigenetics
- Molecular oncology
Background:
- Glioblastomas (GBMs) are aggressive brain tumors with poor prognosis.
- Estrogen Receptor Beta (ERβ) acts as a tumor suppressor in GBM, but its expression is often lost during tumor progression.
- Reversing epigenetic silencing may restore ERβ function and enhance anti-tumor effects.
Purpose of the Study:
- To investigate if epigenetic drugs can re-establish ERβ expression in GBM.
- To evaluate the therapeutic potential of combining epigenetic drugs with an ERβ agonist.
Main Methods:
- Tested inhibitors of histone deacetylases (HDACs), histone methylases, and BET enzymes.
- Utilized RT-qPCR, ChIP, and Western blotting for mechanistic studies.
- Assessed cell viability, apoptosis, colony formation, and invasion in vitro; tested efficacy in an orthotopic GBM model.
Main Results:
- HDAC inhibitors (panobinostat, romidepsin) increased ERβ isoform 1 (tumor-suppressive) expression in GBM cells.
- Combination therapy with HDAC inhibitors and ERβ agonist LY500307 reduced tumor cell viability, invasion, and colony formation, while enhancing apoptosis.
- HDAC inhibitors induced functional ERβ, confirmed by reporter assays and ChIP analysis of target gene promoters.
- Combination therapy in an orthotopic GBM model significantly improved survival.
Conclusions:
- HDAC inhibitors can overcome ERβ suppression in GBM.
- Combination therapy with HDAC inhibitors and LY500307 shows therapeutic promise for GBM treatment.
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