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Histone deacetylase 3 as a novel therapeutic target in multiple myeloma
Open accessAbstract
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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“Finally, an example of the importance of the cap group is highlighted in mocetinostat (Figure 10), where selectivity is gained for HDAC1/2 against HDAC3 (5.5–10.7 fold selective) without resorting to the use of an FT substituent [64].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [64]
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Metadata
- 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.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Anderson, K C
- ORCID
- Venue
- Leukemia
- Published
- 2013-08-05
- Volume
- 28
- Issue
- 3
- Pages
- 680-689
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC4165599
- OpenAlex
- W2004288940
- Cited by
- 159
- References
- 37
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 15 · 2021: 10 · 2020: 15 · 2019: 13 · 2018: 14 · 2017: 16 · 2016: 6 · 2015: 18 · 2014: 8 · 2013: 3
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p01ca078378-15, 5r01ca178264-05)
- U.S. Public Health Service (P50100707)
- National Institute on Drug Abuse (R01 DA02830)
- National Cancer Institute (R01-CA178264, P01-CA-78378, P50CA086355, R01- CA50947, P01-CA078378, P50CA100707, R01CA050947, P01CA155258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- HDAC3, multiple myeloma, HDAC3 inhibitors, STAT3 phosphorylation, STAT3 acetylation, bortezomib combination therapy, apoptosis, caspase activation, poly(ADP-ribose) polymerase, interleukin-6, mesenchymal stem cells, HDAC isoform selectivity, tumor growth inhibition
- MeSH terms
- Histone Deacetylase 3, Cell Division, Histone Deacetylases, Humans, Multiple Myeloma, Cell Line, Tumor, Gene Knockdown Techniques, Histone Deacetylase Inhibitors
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