Histone deacetylase 3 as a novel therapeutic target in multiple myeloma

• Published in: Leukemia Vol. 28; no. 3; pp. 680 - 689
• Main Authors: Minami, J, Suzuki, R, Mazitschek, R, Gorgun, G, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2014; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/67/1990/804; Acetylation; Anticancer properties; Antimitotic agents; Antineoplastic agents; Apoptosis; Biocompatibility; Bone marrow; Bortezomib; Cancer; Cancer Research; Caspase; Cell cycle; Cell Division; Cell growth; Cell Line, Tumor; Clinical trials; Critical Care Medicine; Crosstalk; Cytokines; Cytotoxicity; Diagnosis; Dosage and administration; Drug targeting; Drug therapy; Gene Knockdown Techniques; Hematology; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - drug effects; Histone Deacetylases - genetics; Histones; Humans; Inhibition; Inhibitors; Intensive; Interleukin 6; Internal Medicine; Kinases; Leukemia; Leukemia research; Medicine; Medicine & Public Health; Multiple myeloma; Multiple Myeloma - enzymology; Multiple Myeloma - pathology; Oncology; original-article; Patient outcomes; Penicillin; Phosphorylation; Proteins; Ribose; Side effects; Stat3 protein; Stromal cells; Therapeutic applications; Therapeutic targets; Toxicity; Transcription factors; Transducers; Tumors; Tyrosine; Xenografts; Xenotransplantation; United States > US; Massachusetts; histone deacetylase 3; multiple myeloma; bortezomib; STAT3
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.231

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.