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NF-κB p65 represses microRNA-124 transcription in diffuse large B-cell lymphoma

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Abstract

Background

Previous studies have shown that the copy number of microRNA (miR)-124 is decreased in diffuse large B cell lymphoma (DLBCL), and that miR-124 is a tumor suppressor by targeting NF-κB p65 in B-cell lymphoma. In turn, miR-124 expression is regulated by transcription factors such as HNF4α, ETS2, and p53. However, whether and how miR-124 transcription is modulated by NF-κB transcription factors remain unknown in DLBCL.

Objective

To investigate whether the activation of NF-κB signaling could inhibit the expression of miR-124, possibly contributing to the pathogenesis of DLBCL.

Methods

Potential transcription factors regulating miR-124 transcription were predicted using the Transfac software. The cellular effects of NF-κB p65 on miR-124 were examined by MTS assay, Western blot assay, qPCR, and chromatin immunoprecipitation (ChIP) assays using DLBCL cell lines.

Results

Inhibition of NF-κB signals using Bay11-7085 increased miR-124 expression whereas exposure to TNF-α decreased it. Ectopic expression of p65 suppressed miR-124 expression, suggesting that p65 may be a transcriptional repressor of miRNA-124. Pharmacological analyses showed that phosphorylated/activated p65 downregulates miR-124 via two signaling pathways: (1) TAK1/IKKα-IKKβ/IκBα and (2) MAPK/p65. Moreover, ChIP assay demonstrated that p65 directly regulates miR-124 by binding to the NF-κB consensus sequence in its promoter region. Finally, we also confirmed that stable ectopic expression of miR-124 suppresses cell proliferation and survival.

Conclusion

Taken together, our study uncovered a mechanism by which active NF-κB signaling disrupts the function of miR-124 as a tumor suppressor in DLBCL.

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Acknowledgements

This work was supported by a two-year Research Grant to Pusan National University.

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Authors and Affiliations

  1. Department of Biological Sciences, Pusan National University, Pusan, 46241, Republic of Korea

    Hyein Shim, Jehyun Nam & Sang-Woo Kim

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  1. Hyein Shim
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  2. Jehyun Nam
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  3. Sang-Woo Kim
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Hyein Shim, Jehyun Nam and Sang-Woo Kim. The first draft of the manuscript was written by Hyein Shim and Sang-Woo Kim. All authors read and approved the final manuscript.

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Correspondence to Sang-Woo Kim.

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Hyein Shim, Jehyun Nam and Sang-Woo Kim declare that they have no conflict of interest.

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Shim, H., Nam, J. & Kim, SW. NF-κB p65 represses microRNA-124 transcription in diffuse large B-cell lymphoma. Genes Genom 42, 543–551 (2020). https://doi.org/10.1007/s13258-020-00922-y

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  • DOI: https://doi.org/10.1007/s13258-020-00922-y

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