Abstract
Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.
Highlights
Introduction GlioblastomaMultiforme (GBM), known as WHO grade IV malignant glioma, is the most common and malignant primary brain tumor in adults[1]
These analyses showed that high levels of HDAC1 and Histone deacetylase 6 (HDAC6) correlated with decreased survival and advanced glioma grade in Rembrandt and TCGA, as well as additional cohorts (Fig. 1c, d and Supplementary Fig. 1b–d)
Immunoblot analysis confirmed that both proteins were expressed in majority of GBM cell lines and, in particular, HDAC6 was highly expressed in glioma stem cell (GSC) (Fig. 1e)
Summary
Introduction GlioblastomaMultiforme (GBM), known as WHO grade IV malignant glioma, is the most common and malignant primary brain tumor in adults[1]. The GBM epigenome presents both specific and general shifts in the histone-modification and DNA methylation landscapes[9,10] In this regard, epigenetic alterations have become promising GBM diagnostic biomarkers and therapeutic targets since, unlike genetic mutations, the effect of epigenetic modifications might be reversible by the use of drugs that target enzymes involved in adding, removing, or signaling histone modifications and DNA methylation[9,11,12]. Epigenetic alterations have become promising GBM diagnostic biomarkers and therapeutic targets since, unlike genetic mutations, the effect of epigenetic modifications might be reversible by the use of drugs that target enzymes involved in adding, removing, or signaling histone modifications and DNA methylation[9,11,12] In this line, inhibitors of histone deacetylases (HDACs) and DNA demethylating agents have been approved for use in the therapy of hematologic malignancies, such as cutaneous T-cell lymphoma and myelodysplastic syndrome, respectively[12]. The lack of specificity of some of these compounds still remains a clinical issue since high and, for some cases, active doses elicit deleterious side effects
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