Bromodomain inhibitor jq1 induces cell cycle arrest and apoptosis of glioma stem cells through the VEGF/PI3K/AKT signaling pathway

Wen,Naiyan; Guo,Baofeng; Zheng,Hongwu; Xu,Libo; Liang,Hang; Wang,Qian; Wang,Ding; Chen,Xuyang; Zhang,Shengnan; Li,Yang; Zhang,Ling

doi:10.3892/ijo.2019.4863

Bromodomain inhibitor jq1 induces cell cycle arrest and apoptosis of glioma stem cells through the VEGF/PI3K/AKT signaling pathway

Authors:
- Naiyan Wen
- Baofeng Guo
- Hongwu Zheng
- Libo Xu
- Hang Liang
- Qian Wang
- Ding Wang
- Xuyang Chen
- Shengnan Zhang
- Yang Li
- Ling Zhang
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Affiliations: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Plastic Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
Published online on: August 29, 2019 https://doi.org/10.3892/ijo.2019.4863
Pages: 879-895
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bromodomain and extraterminal domain proteins, especially bromodomain‑containing protein 4 (Brd4), have recently emerged as therapeutic targets for several cancers, although the role and mechanism of Brd4 in glioblastoma multiforme (GBM) are unclear. In this study, we aimed to explore the underlying mechanisms of the anti‑tumor effects of Brd4 and the bromodomain inhibitor JQ1 on glioma stem cells (GSCs). In vitro, JQ1 and small interfering RNAs targeting Brd4 (siBrd4) inhibited the proliferation and self‑renewal of GSCs. In vivo, JQ1 significantly inhibited the growth of xenograft GSCs tumors. The RNA‑seq analysis revealed that the PI3K‑AKT pathway played an important role in GBM. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 phosphorylation was downregulated by exposure to JQ1 in GSCs, thereby reducing PI3K and AKT activity. In addition, treatment with JQ1 inhibited MMP expression, thereby inhibiting degradation of the extracellular matrix by MMP and angiogenesis in GBM tumors. Suppression of AKT phosphorylation inhibited the expression of the retinoblastoma/E2F1 complex, resulting in cell cycle arrest. In addition, treatment with siBrd4 or JQ1 induced apoptosis by activating AKT downstream target genes involved in apoptosis. In conclusion, these results suggest that Brd4 has great potential as a therapeutic target, and JQ1 has notable anti‑tumor effects against GBM which may be mediated via the VEGF/PI3K/AKT signaling pathway.

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