Suberoylanilide Hydroxamic Acid-Mediated Repression of Temozolomide Resistant Cells in Glioblastoma Multiforme

[Speaker] Chiung-Yuan Ko:1
[Co-author] Yu-Ting Tsai:2, Jian-Ying Chuang:1, Wen-Chang Chang:2
1:The PH. D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, 11031, Taiwan, 2:Graduate Institute of Medical Sciences, Taipei Medical University Taipei, 11031, Taiwan

Introduction:Glioblastoma multiforme (GBM), known as a grade IV astrocytoma, is the most aggressive brain tumor. Although GBM patients receive the standard treatment including surgery, radiation therapy, and chemotherapy, they are never considered curable and the tumors become more resistant to therapy. Recently, glioma stem-like cells (GSCs) have been correlated with therapeutic resistance. In which, several genes, such as B lymphoma Mo-MLV insertion region 1 (Bmi-1), are upregulated and control stemness-related features including multi-drug resistance.
Method:In this study, we focused on an agent suberoylanilide hydroxamic acid (SAHA) with functions in altering gene expression by the inhibition of histone deacetylases, and found that attenuated viability of GSCs and temozolomide (TMZ)-resistant GBM cells via decreasing Bmi-1 levels. We used reporter assay, DNA affinity pull down assay (DAPA), and immunoprecipitation (IP) to investigate the molecular mechanisms.
Results:Sp1 acted as an essential upstream regulator of Bmi-1, but SAHA attenuated Sp1 acetylation and its expression resulting in the reduction of Bmi-1 transcription.
Conclusion:Our results provide a perspective on combining SAHA with TMZ to inhibit GCSs and to enhance TMZ sensitivity in drug-resistant GBM.

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