BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Open accessAbstract
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs.
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miR-106b-5p is an oncogenic miRNA that appears to be upregulated in hepatic cancer, cervical cancer, gliomas, and gastric cancer.
“miR-106b-5p is an oncogenic miRNA that appears to be upregulated in different cancers, such as hepatic cancer,232 cervical cancer,233 gliomas,234 and gastric cancer.235”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [235]
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- Authors
- Dong, X., Hu, X., Chen, J., Hu, D., & Chen, L.-F.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Fujian Medical University (CN)
- Corresponding author
- Chen, Lin-Feng
- Venue
- Cell Death & Disease
- Published
- 2018-02-12
- Volume
- 9
- Issue
- 2
- Pages
- 203-203
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5833665
- OpenAlex
- W2789307901
- Cited by
- 75
- References
- 65
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 3
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (DK085158, CA179511)
- University of Illinois at Urbana-Champaign
- National Cancer Institute (R01CA179511)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BRD4, BET proteins, JQ1, BET inhibitors, cellular senescence, gastric cancer, miR-106b-5p, p21, E2F transcription factors, post-transcriptional regulation, 3' untranslated region, cell proliferation, cell invasion
- MeSH terms
- Bromodomain Containing Proteins, Female, Humans, Male, Neoplasm Proteins, Nuclear Proteins, Stomach Neoplasms, Transcription Factors, Cellular Senescence, Cell Cycle Proteins, MicroRNAs, Cell Line, Tumor, E2F Transcription Factors, Cyclin-Dependent Kinase Inhibitor p21
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