Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells

Dante Rotili,Halina Was,Marta Maleszewska,Antonello Mai,Bartosz Wojtas,Bozena Kaminska,Sylwia K. Krol

doi:10.1186/s13148-018-0598-5

Abstract

BackgroundThe diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility. Nevertheless, the impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined.ResultsComprehensive analysis of the public TCGA dataset revealed the increased expression of HDAC 1, 2, 3, and 7 in malignant gliomas. Knockdown of HDAC 1 and 2 in human GBM cells significantly decreased cell proliferation. We tested the activity of 2 new and 3 previously described HDACi with different class/isoform selectivity on human GBM cells. All tested compounds exerted antiproliferative properties on glioma cells. However, the HDACi 1 and 4 blocked proliferation of glioblastoma cells leading to G2/M growth arrest without affecting astrocyte survival. Moreover, 1 and 4 at low micromolar concentrations displayed cytotoxic and antiproliferative effects on sphere cultures enriched in glioma stem cells.ConclusionsWe identified two selective HDAC inhibitors that blocked proliferation of glioblastoma cells, but did not affect astrocyte survival. These new and highly effective inhibitors should be considered as promising candidates for further investigation in preclinical GBM models.

Highlights

The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis
Selected histone deacetylases (HDAC) are overexpressed in human glioblastomas The TCGA (The Cancer Genome Atlas) low-grade glioma (LGG) and GBM cohorts consist of 516 and 606 patients, respectively [7, 17]
By using RNA-sequencing data from the public TCGA database, the expression of the genes coding for HDAC 1–11 in five normal brains and a large group of gliomas of different World Health Organization (WHO) grades (GII-III-IV) was analyzed

Summary

Introduction

The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. The impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined. Glioblastoma (GBM, WHO grade IV) is the most common and aggressive primary tumor of the brain [1, 2]. The median survival of patients with GBM is only 12.1–14.6 months from the time of diagnosis [5]. Recent findings from large-scale profiling including whole exome and RNA sequencing have revealed that both genetic and epigenetic mechanisms are significantly deregulated in glioma cells [6, 7].

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