Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Yiru ZhangMarkus D Siegelin

Abstract

Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing ...Continue Reading

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Citations

Mar 3, 2020·Expert Opinion on Drug Discovery·Abdallah Hamze
Dec 6, 2018·Oncotarget·Yiru ZhangMarkus D Siegelin
Dec 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Floris J van DalenOlga Ilina
Jul 20, 2020·Journal of Experimental & Clinical Cancer Research : CR·Rui ChenYali Wang
Sep 12, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yu-Cheng ChouJing-Gung Chung
Apr 20, 2021·Life Sciences·M Janaki RamaiahRajasekhar Reddy Manyam
Jun 1, 2021·Signal Transduction and Targeted Therapy·Lei ZhongShengyong Yang
Jun 10, 2021·European Journal of Medicinal Chemistry·Ying-Chao DuanYuan-Yuan Guan

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