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Multiple Myeloma, Gammopathies

HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications

Leukemia volume 31, pages 2670–2677 (2017)Cite this article

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Abstract

Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.

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Acknowledgements

This study was supported by the National Institute of Health Grants SPORE-P50100707 (KCA), P01-CA078378 (KCA), R01-CA050947 (KCA), and R01-CA178264 (T Hideshima and KCA). KCA is an American Cancer Society Clinical Research Professor.

Author contributions

T Harada, HO and T Hideshima designed the research. T Harada performed experiments. YG performed the bioinformatics analysis. RM synthesized BG45. T Harada, HO, SK, MS, T Hideshima and KCA analyzed the data. YT and KCA provided MM patient samples. HO, T Hideshima and KCA supervised the study. T Harada, HO, YG, T Hideshima and KCA wrote the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    T Harada, H Ohguchi, S Kikuchi, M Sagawa, Y-T Tai, T Hideshima & K C Anderson

  2. Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Y Grondin

  3. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA

    R Mazitschek

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Correspondence to K C Anderson.

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Harada, T., Ohguchi, H., Grondin, Y. et al. HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31, 2670–2677 (2017). https://doi.org/10.1038/leu.2017.144

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