Inhibition of the HDAC6/Sp1 pathway by azaindolylsulfonamide reduces cancer stemness and restores treatment susceptibility in glioblastoma

[Speaker] Jian-Ying Chuang:1
[Co-author] Che-Chia Hsu:2, Kwang-Yu Chang:3, Wen-Chang Chang:2
1:The Ph. D. Program for Neural Regenerative Medicine, Taipei Medical University, Taiwan, 2:Graduate Institute of Medical Sciences, Taipei Medical University, Taiwan, 3:National Institute of Cancer Research, National Health Research Institutes, Taiwan

Glioblastoma (GBM), known as a highly aggressive brain tumor, has extremely poor prognosis and high mortality even following standard treatment with surgery, radiotherapy, and chemotherapy using the first-line agent temozolomide (TMZ). Treatment resistance and recurrence are the most known challenges in tumor therapies, and that have an association with an abundant source of cancer stem-like cells (CSCs). Therefore, to find new strategies aimed at reducing therapeutic resistance and cancer stemness in GBM become imperative. We investigated the therapeutic resistance using TMZ-resistant cells and CSCs-enriched cultures, and found a correlation between histone deacetylase 6 (HDAC6) activity and the expression of stemness genes and human telomerase reverse transcriptase (hTERT). However, these genes downregulated by a potent and selective HDAC6 inhibitor, azaindolylsulfonamide, significantly reduced the resistant cells. Investigation of promoters of stemness genes (CD133, BMI1, NANOG) and hTERT revealed Sp1 as a critical transcriptional activator. Sp1 overexpression restored the inhibitory effects of azaindolylsulfonamide, and increased CD133 and hTERT levels in TMZ-resistant cells. Furthermore, we found that azaindolylsulfonamide treatment restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that HDAC6 modulates Sp1 transcriptional activator as a novel mechanism to increase cancer stemness and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.
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