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BRD4 regulates self-renewal ability and tumorigenicity of glioma-initiating cells by enrichment in the Notch1 promoter region.

ABSTRACT: Bromodomain and extraterminal domain (BET) family proteins are considered to be epigenetic readers that regulate gene expression by recognizing acetyl lysine residues on histones and nonhistone chromatin factors and have been classified as curative targets for a variety of cancers. Glioma-initiating cells (GICs), which commit self-renewal, perpetual proliferation, multidirectional differentiation, and vigorous tumorigenicity, sustain the peculiar genetic and epigenetic diversification in the GBM patients, thus, GICs result in tumor recurrence. Abundant evidence demonstrates that BET proteins regulate differentiation of stem cells. However, it endures ambiguous how individual BET proteins take part in GIC advancement, and how do small molecule inhibitors like I-BET151 target functional autonomous BET proteins. Here, we validated that BRD4, not BRD2 or BRD3, has value in targeted glioma therapy. We announce a signaling pathway concerning BRD4 and Notch1 that sustains the self-renewal of GICs. Moreover, in-depth mechanistic research showed that BRD4 was concentrated at the promoter region of Notch1 and may be involved in the process of tumor metabolism. Furthermore, in intracranial models, I-BET151 eliminated U87 GICs' tumorigenicity. The outcomes of this research could be conducive to design clinical trials for treatment of glioma based on BRD4.

SUBMITTER: Tao Z

PROVIDER: S-EPMC7533052 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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BRD4 regulates self-renewal ability and tumorigenicity of glioma-initiating cells by enrichment in the Notch1 promoter region.

Tao Zhennan Z Li Xuetao X Wang Hao H Chen Guangliang G Feng Zibin Z Wu Yue Y Yin Haoran H Zhao Guozheng G Deng Zhitong Z Zhao Chaohui C Li Yanyan Y Sun Ting T Zhou Youxin Y

Clinical and translational medicine 20201001 6

Bromodomain and extraterminal domain (BET) family proteins are considered to be epigenetic readers that regulate gene expression by recognizing acetyl lysine residues on histones and nonhistone chromatin factors and have been classified as curative targets for a variety of cancers. Glioma-initiating cells (GICs), which commit self-renewal, perpetual proliferation, multidirectional differentiation, and vigorous tumorigenicity, sustain the peculiar genetic and epigenetic diversification in the GBM ...[more]

PMID: 33135348

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Project description:BackgroundGlioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms.MethodsBioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in GBM samples. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. Luciferase reporter assay was used to testify the potential binding site of Notch1 signaling and CXCR4. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo.ResultsNotch1 signaling activity was elevated in GBM tissues. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Furthermore, downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal, invasion and tumor growth ability of GICs.ConclusionsThese findings suggest that the cross-talk between Notch1 signaling and CXCL12/CXCR4 system could contribute to the self-renewal and invasion of GICs, and this discovery could help drive the design of more effective therapies in Notch1-targeted treatment of GBMs.

Dataset Information

BRD4 regulates self-renewal ability and tumorigenicity of glioma-initiating cells by enrichment in the Notch1 promoter region.

Publications

BRD4 regulates self-renewal ability and tumorigenicity of glioma-initiating cells by enrichment in the Notch1 promoter region.

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