HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications
Open accessAbstract
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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In multiple myeloma, HDAC3 deacetylates DNMT1, increasing its stability.
“In multiple myeloma (MM), HDAC3 deacetylates DNMT1, thereby increasing its stability.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Harada et al., 2017
Another non-histone target of HDAC3 in cancer is DNMT1.
“Another non-histone target of HDAC3 that plays a role in cancer is DNA methyltransferase 1 (DNMT1).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Harada et al., 2017
DNMT1 is required to maintain proliferation of multiple myeloma.
“DNMT1 is required to maintain the proliferation of MM.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Harada et al., 2017
Inhibiting both HDAC3 and DNMT1 with their respective inhibitors will have a more potent anti-proliferative effect.
“Thus, inhibiting both HDAC3 and DNMT1 with their respective inhibitors will have a more potent anti-proliferative effect (Harada et al., 2017).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Harada et al., 2017
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- Authors
- Harada, T., Ohguchi, H., Grondin, Y., Kikuchi, S., Sagawa, M., Tai, Y.-T., Mazitschek, R., Hideshima, T., & Anderson, K. C.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Anderson, K C
- Venue
- Leukemia
- Published
- 2017-05-11
- Volume
- 31
- Issue
- 12
- Pages
- 2670-2677
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC5681897
- OpenAlex
- W2613870926
- Cited by
- 89
- References
- 42
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 6 · 2017: 2
- FWCI
- 3.80
- 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)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Funders
- National Institutes of Health (5p01ca078378-15, 5r01ca178264-05)
- National Cancer Institute (R01-CA178264, 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 › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HDAC3, DNMT1, multiple myeloma, histone deacetylase inhibitors, azacitidine, c-Myc, protein stability, DNA methylation, epigenetic regulation, combination therapy, drug synergy, apoptosis, histone acetylation
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Histone Deacetylase 3, Acetylation, Animals, Disease Models, Animal, Histone Deacetylases, Humans, Models, Biological, Multiple Myeloma, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Apoptosis, Gene Expression Profiling, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Mice, Protein Stability, Gene Knockdown Techniques, Histone Deacetylase Inhibitors
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