Suberoylanilide hydroxamic acid represses glioma stem-like cells.

Che-Chia Hsu,Jing-Ping Liou,Kwang-Yu Chang,Jian-Ying Chuang,Jia-Yi Wang,Chiung-Yuan Ko,Wen-Chang Chang,Jr-Jiun Liu,Shiu-Hwa Yeh,Tsung-I Hsu

doi:10.1186/s12929-016-0296-6

Abstract

BackgroundGlioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.MethodsHuman GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.ResultsWe demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.ConclusionSAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0296-6) contains supplementary material, which is available to authorized users.

Highlights

Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment
suberoylanilide hydroxamic acid (SAHA) suppresses cell viability/proliferation and stemnessrelated markers in GSCs To elucidate the effects of SAHA on GSCs, we used sphere cultures to induce spheroid bodies formation from U87MG (Fig. 1a) and U373MG (Additional file 1: Figure S1A) GBM cells, since a spheroid environment can be employed to enrich cancer stem-like cell (CSC) [25, 26]
We demonstrated that SAHA suppressed cell proliferation and diminished stemness properties in GSCs

Summary

Introduction

Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Glioblastoma multiforme (GBM) has a high recurrence and mortality. The median survival time after a combination of radiotherapy and adjunct temozolomide (TMZ) treatment is only about 14.6 months due to frequent tumor relapse after surgical removal [1]. GBM tumor cells are highly invasive, proliferate rapidly, and display resistance to chemotherapy and irradiation. The aggressiveness and high malignancy of GBM are linked to an abundant source of glioma stem-like cells (GSCs) [2].

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