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  3. A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis

A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis

  • Mol Cancer Ther. 2020 Dec;19(12):2542-2553. doi: 10.1158/1535-7163.MCT-20-0037.
Qian Wang 1,  Shengnan Jia 2,  Ding Wang 1,  Xuyang Chen 1,  Dhan V Kalvakolanu 3,  Hongwu Zheng 4,  Xiaodong Wei 1,  Naiyan Wen 1,  Hang Liang 1,  Baofeng Guo 5,  Ling Zhang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 2 Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun, China.
  • 3 Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology University of Maryland School Medicine, Baltimore, Maryland.
  • 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
  • 5 Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China. zhangling3@jlu.edu.cn gbf@jlu.edu.cn.
  • 6 Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China. zhangling3@jlu.edu.cn gbf@jlu.edu.cn.
PMID: 32999044 DOI: 10.1158/1535-7163.MCT-20-0037
Abstract

Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 Inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored whether cotreatment with a BRD4 Inhibitor, JQ1 (BRD4i), in GSCs produced a better antitumor effect. BRD4i synergistically inhibits GSC 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 IL6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of the GLI1 gene, thereby blocking the GLI1/IL6/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.

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