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Myeloma

Histone deacetylase 3 as a novel therapeutic target in multiple myeloma

Leukemia volume 28, pages 680–689 (2014)Cite this article

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Abstract

Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable antitumor activities in the preclinical setting; however, their clinical utility is limited because of unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small-molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and poly (ADP-ribose) polymerase cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of signal transducers and activators of transcription 3 (STAT3). Neither interleukin-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on phospho-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or 2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.

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Acknowledgements

This study was supported by the National Institute of Health Grants (SPORE-P50100707, P01 CA78378, R01 CA50947 (KCA), R01 DA02830 (SJH) and P50CA086355 (RM)). KCA is an American Cancer Society Clinical Research Professor.

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Author notes

  1. J Minami and R Suzuki: These authors contributed equally to this work.

Authors and Affiliations

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

    J Minami, R Suzuki, G Gorgun, D Cirstea, Y Hu, N Mimura, H Ohguchi, F Cottini, J Jakubikova, N C Munshi, P G Richardson, T Hideshima & K C Anderson

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

    R Mazitschek & B Ghosh

  3. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    B Ghosh & S J Haggarty

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  1. J Minami
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Corresponding author

Correspondence to K C Anderson.

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Competing interests

RM has financial interests in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals. He is also the inventor on IP licensed to these two entities. PGR is a member of advisory board for Celgene, Millennium, Johnson & Johnson, Novartis and Keryx. TH is a consultant for Acetylon Pharmaceuticals. KCA is a member of advisory committees for Onyx, Celgene, Gilead and Sanofi-Aventis, and is a scientific founder of Acetylon and Oncopep. The other authors declare no conflict of interest.

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Minami, J., Suzuki, R., Mazitschek, R. et al. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia 28, 680–689 (2014). https://doi.org/10.1038/leu.2013.231

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