Histone deacetylase 3 as a novel therapeutic target in multiple myeloma

J. Minami, R. Suzuki, R. Mazitschek, Gullu Gorgun, B. Ghosh, D. Cirstea, Y. Hu, N. Mimura, H. Ohguchi, F. Cottini, J. Jakubikova, N. C. Munshi, S. J. Haggarty, P. G. Richardson, T. Hideshima, K. C. Anderson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)680-689
Number of pages10
JournalLeukemia
Volume28
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Multiple Myeloma
STAT3 Transcription Factor
Histone Deacetylases
Therapeutics
Growth
Phosphorylation
Poly(ADP-ribose) Polymerases
Acetylation
Caspases
Mesenchymal Stromal Cells
Heterografts
Serine
Tyrosine
histone deacetylase 3
Interleukin-6
Neoplasms
Protein Isoforms
Down-Regulation
Apoptosis

Keywords

  • Bortezomib
  • Histone deacetylase 3
  • Multiple myeloma
  • STAT3

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Minami, J., Suzuki, R., Mazitschek, R., Gorgun, G., Ghosh, B., Cirstea, D., ... Anderson, K. C. (2014). Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia, 28(3), 680-689. https://doi.org/10.1038/leu.2013.231

Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. / Minami, J.; Suzuki, R.; Mazitschek, R.; Gorgun, Gullu; Ghosh, B.; Cirstea, D.; Hu, Y.; Mimura, N.; Ohguchi, H.; Cottini, F.; Jakubikova, J.; Munshi, N. C.; Haggarty, S. J.; Richardson, P. G.; Hideshima, T.; Anderson, K. C.

In: Leukemia, Vol. 28, No. 3, 2014, p. 680-689.

Research output: Contribution to journalArticle

Minami, J, Suzuki, R, Mazitschek, R, Gorgun, G, Ghosh, B, Cirstea, D, Hu, Y, Mimura, N, Ohguchi, H, Cottini, F, Jakubikova, J, Munshi, NC, Haggarty, SJ, Richardson, PG, Hideshima, T & Anderson, KC 2014, 'Histone deacetylase 3 as a novel therapeutic target in multiple myeloma', Leukemia, vol. 28, no. 3, pp. 680-689. https://doi.org/10.1038/leu.2013.231
Minami J, Suzuki R, Mazitschek R, Gorgun G, Ghosh B, Cirstea D et al. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia. 2014;28(3):680-689. https://doi.org/10.1038/leu.2013.231
Minami, J. ; Suzuki, R. ; Mazitschek, R. ; Gorgun, Gullu ; Ghosh, B. ; Cirstea, D. ; Hu, Y. ; Mimura, N. ; Ohguchi, H. ; Cottini, F. ; Jakubikova, J. ; Munshi, N. C. ; Haggarty, S. J. ; Richardson, P. G. ; Hideshima, T. ; Anderson, K. C. / Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. In: Leukemia. 2014 ; Vol. 28, No. 3. pp. 680-689.
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