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Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas

Oncogene volume 31, pages 3002–3008 (2012)Cite this article

Abstract

Our recent study demonstrated miR-15a/16-1 downregulation in mantle cell lymphoma (MCL). Here, we investigated mechanisms of miR-15a/16-1 transcriptional repression and its epigenetic regulation by c-Myc and histone deacetylase (HDAC) in MCL. c-Myc expression was detected in MCL cell lines and in the primary MCL samples, and pri-miR-15a/16-1 mRNAs were significantly upregulated in Mino and Jeko-1 cells with c-Myc knockdown by small interfering RNAs (siRNAs). Our co-immunoprecipitation analysis showed that c-Myc interacted with HDAC3. Moreover, using chromatin immunoprecipitation, we demonstrated that both c-Myc and HDAC3 co-localized to the two promoters of the miR-15a/16-1 cluster gene, DLEU2, and inhibition of HDAC3 increased histone acetylation of the DLEU2 promoters. Luciferase reporter assay confirmed the dependence of Myc-mediated DLEU2 transcriptional repression on HDAC3. Treatment with the pan-HDAC inhibitor, suberoylanilide hydroxamic acid and HDAC3 siRNA resulted in increased miR-15a/16-1 expression. The regulatory mechanism of miR-15a/16-1 was further demonstrated in Burkitt lymphoma and Myc overexpressing cell lines. These findings highlight the role of HDAC3 in Myc-induced miR-15a/16-1 changes and reveal novel mechanisms for c-Myc-driven microRNA suppression and malignant transformation in aggressive B-cell malignancies.

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Acknowledgements

We are grateful to the Tissue Procurement, Molecular Core Laboratory and Flow Cytometry Core Facilities at H Lee Moffitt Cancer Center for providing specimens and molecular analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institutes (R01 CA137123, to JT), Maher Fund (to JT) and Moffitt Cancer Center Foundation (to JT).

 Author contributions: XZ and XC designed and performed all of the experiments and contributed to manuscript preparation; ES and KW provided essential reagents and intellectual support; JL, TL and GW contributed to miRNA and ChIP analysis. ES, LM, WD, KW and JT provided clinical samples, information and intellectual support; XZ and JT designed experiments, interpreted data and wrote the manuscript.

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  1. X Chen

    Present address: Current address: Tianjin Eye Hospital, Tianjin Medical University, Tianjin, China.,

  2. X Zhang and X Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA

    X Zhang, X Chen, J Lin, T Lwin, G Wright, L C Moscinski, W S Dalton, E Seto, K Wright, E Sotomayor & J Tao

  2. Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China

    X Zhang

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Zhang, X., Chen, X., Lin, J. et al. Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31, 3002–3008 (2012). https://doi.org/10.1038/onc.2011.470

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