Inhibition of histone deacetylase 6 by tubastatin A as an experimental therapeutic strategy against glioblastoma
Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery, temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs) are being explored against a variety of...
| Authors: | , , , , , , |
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| Format: | article |
| Publication Date: | 2021 |
| Country: | España |
| Institution: | Universidad de Navarra |
| Repository: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Language: | English |
| OAI Identifier: | oai:dadun.unav.edu:10171/115880 |
| Online Access: | https://hdl.handle.net/10171/115880 |
| Access Level: | Open access |
| Keyword: | Autophagy Epithelial‑to‑mesenchymal transition Glioblastoma Histone deacetylase 6 Sonic Hedgehog pathway Tubastatin A |
| Summary: | Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery, temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs) are being explored against a variety of tumors, including glioblastoma. Specific inhibitors of HDAC6, such as tubastatin A (Tub A), may potentially be beneficial as HDAC6 has been demonstrated to be the most expressed HDACs in glioblastoma. Our aim was to test whether Tub A could reverse the malignant phenotype of U87MG cells via the inhibition of HDAC6. Materials and Methods: U87MG cells were treated with cyclopamine (Cyp), TMZ, and Tub A. Two double treatments were performed as well (Cyp + Tub A and TMZ + Tub A). Colony formation, wound healing, Caspase‑Glo 3/7, quantitative reverse transcription–polymerase chain reaction, luciferase assay, and Western blot assays were conducted to determine clonogenic and migration capacity, apoptosis, activation of the Sonic Hedgehog pathway, acetylation of α‑tubulin and epithelial‑to‑mesenchymal transition, and autophagic flux of U87MG glioblastoma cells, respectively. Results: Tub A treatment caused a reversal of the U87MG malignant phenotype by reducing its clonogenic and migratory cellular potential, and inducing apoptosis. Sonic Hedgehog pathway inhibition, together with reversal of epithelial‑to‑mesenchymal transition and reduced autophagic flux, was also induced by the effect of Tub A. Conclusions: HDAC6 might be a good target for glioblastoma treatment. |
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