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MicroRNA-16 mediates the regulation of a senescence–apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas

Oncogene volume 35, pages 3692–3704 (2016)Cite this article

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Abstract

Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence–apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.

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Acknowledgements

We wish to express our appreciation to Mr J Yamashita for his outstanding technical assistance. This work was supported by JSPS KAKENHI Grant Number 25461405 (Grant-in-Aid for Scientific Research (to HT)) and a Grant from the Uehara Memorial Foundation.

Author contributions

AK, SI, MI, KT, IT, NH, NT, TM and MS and HT performed experiments and analyzed data. AK and HT designed experiments, analyzed data and wrote the paper. HT designed the study.

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Authors and Affiliations

  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    A Kitadate, S Ikeda, K Teshima, M Ito, I Toyota, N Takahashi & H Tagawa

  2. Department of Dermatology, Akita University, Akita, Japan

    N Hasunuma

  3. Department of Dermatology, University of Tokyo, Tokyo, Japan

    T Miyagaki & M Sugaya

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  1. A Kitadate
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Correspondence to H Tagawa.

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Kitadate, A., Ikeda, S., Teshima, K. et al. MicroRNA-16 mediates the regulation of a senescence–apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas. Oncogene 35, 3692–3704 (2016). https://doi.org/10.1038/onc.2015.435

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