A combination of BRD4 and HDAC3 inhibitors synergistically suppresses glioma stem cell growth by blocking GLI1/IL-6/STAT3 signaling axis.

Glioma stem cells (GSCs) are essential for tumor maintenance, invasiveness and recurrence. Using a global epigenetic screening with a shRNA library, we identified HDAC3 as essential factor for GSCs stemness. Here we demonstrated GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL-6 and STAT3 activation. To enhance GSCs sensitivity to HDAC3i, we explored if co-treatment with a BRD4 inhibitor, JQ1 (BRD4i) in GSCs produced a better anti-tumor effect. BRD4i synergistically inhibits GSCs growth in association with HDAC3i. HDAC3 inhibition upregulated the acetylation of H3K27 which allowed the recruitment of BRD4 to the GLI1 gene promoter and induced its expression. GLI1, a transcription factor, turned on the expression of IL-6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of GLI1 gene, thereby blocked GLI1/IL-6/STAT3 pathway. In vivo, the HDAC3i/BRD4i combination caused stronger tumor growth suppression than either drug alone. Thus, HDAC3i/BRD4i might provide promising therapies for GBM.