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Comprehensive analysis of microRNAs modulated by histone deacetylase inhibitors identifies microRNA-7-5p with anti-myeloma effect

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Abstract

Basic research to expand treatment options for multiple myeloma is greatly needed due to the refractory nature of the disease. Histone deacetylase (HDAC) inhibitors, which are epigenetic regulators, are attractive but have limited applications. MicroRNAs (miRNAs), which are also epigenetic regulators, are important molecules that may lead to future therapeutic breakthroughs. In this study, we comprehensively searched for miRNAs that are altered by HDAC inhibitors in myeloma cells. We identified miR-7-5p (miR-7) as a miRNA downregulated by HDAC inhibitors. Transfection of myeloma cell lines with miR-7 suppressed cell proliferation, induced apoptosis, and enhanced the effects of the HDAC inhibitor panobinostat. Expression of miR-7 was downregulated by c-Myc inhibition, but upregulated by bortezomib. Comprehensive examination of miR-7 targets revealed four candidates: SLC6A9, LRRC59, EXOSC2, and PSME3. Among these, we focused on PSME3, an oncogene involved in proteasome capacity in myeloma cells. PSME3 knockdown increases myeloma cell death and panobinostat sensitivity. In conclusion, miR-7, which is downregulated by HDAC inhibitors, is a tumor suppressor that targets PSME3. This miR-7 downregulation may be involved in HDAC inhibitor resistance. In addition, combinations of anti-myeloma drugs that complement changes in miRNA expression should be considered.

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Acknowledgements

The authors thank Yukiko Abe, Yuko Chiba, and Hiromi Kataho for technical assistance. The authors also thank Honyaku Center Inc. for English language editing. This study was supported by JSPS KAKENHI (Grant number: 17K16179).

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Authors and Affiliations

  1. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Akita, 0108543, Japan

    Masahiro Yamada, Sho Ikeda, Wataru Kuroki, Akihiro Kitadate, Hiroyuki Tagawa & Naoto Takahashi

  2. Department of Life Science, Graduate School of Engineering Science, Akita University, Akita, Japan

    Sayaka Iwama & Yuto Takahashi

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  1. Masahiro Yamada
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  2. Sho Ikeda
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Contributions

Masahiro Yamada, Sho Ikeda, Wataru Kuroki, Sayaka Iwama, Yuto Takahashi, and Akihiro Kitadate performed experiments and analyzed data. Sho Ikeda and Masahiro Yamada drafted the manuscript. Sho Ikeda and Hiroyuki Tagawa designed this study. Naoto Takahashi supervised the research.

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Correspondence to Sho Ikeda.

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Conflict of interest

Sho Ikeda: Honoraria, Janssen Pharma, Akihiro Kitadate: Honoraria, Janssen Pharma and Sanofi, Naoto Takahashi: Honoraria, Novartis Pharma; Research funding, Takeda Pharmaceutical Company, Kyowa Hakko Kirin, and Novartis Pharma.

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Yamada, M., Ikeda, S., Kuroki, W. et al. Comprehensive analysis of microRNAs modulated by histone deacetylase inhibitors identifies microRNA-7-5p with anti-myeloma effect. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03812-1

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  • DOI: https://doi.org/10.1007/s12185-024-03812-1

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