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EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma–Induced Epigenetic Suppression of Osteoblast Differentiation
Open accessAbstract
In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that multiple myeloma cells induce repressive epigenetic histone changes at the Runx2 locus that prevent osteoblast differentiation. The most pronounced multiple myeloma–induced changes were at the Runx2-P1 promoter, converting it from a poised bivalent state to a repressed state. Previously, it was observed that multiple myeloma induces the transcription repressor GFI1 in osteoblast precursors, which correlates with decreased Runx2 expression, thus prompting detailed characterization of the multiple myeloma and TNFα-dependent GFI1 response element within the Runx2-P1 promoter. Further analyses reveal that multiple myeloma–induced GFI1 binding to Runx2 in osteoblast precursors and recruitment of the histone modifiers HDAC1, LSD1, and EZH2 is required to establish and maintain Runx2 repression in osteogenic conditions. These GFI1-mediated repressive chromatin changes persist even after removal of multiple myeloma. Ectopic GFI1 is sufficient to bind to Runx2, recruit HDAC1 and EZH2, increase H3K27me3 on the gene, and prevent osteogenic induction of endogenous Runx2 expression. Gfi1 knockdown in MC4 cells blocked multiple myeloma–induced recruitment of HDAC1 and EZH2 to Runx2, acquisition of repressive chromatin architecture, and suppression of osteoblast differentiation. Importantly, inhibition of EZH2 or HDAC1 activity in pre-osteoblasts after multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma reversed the repressive chromatin architecture at Runx2 and rescued osteoblast differentiation. Implications: This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma–induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405–17. ©2017 AACR.
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“Adamik and colleagues discovered that there is an aberrant activation of chromatin remodelers in MSCs from myeloma patients. This abnormal activation ends with the suppression of Runx2, a key regulator of osteoblast development.”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [136]
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“In this regard, Adamik et al., showed that the repressive chromatin architecture at Runx2 was reversed and osteoblast differentiation was salvaged when EZH2 or HDAC1 activity was inhibited in pre-osteoblasts following multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma [136].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [136]
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BackgroundA model for transmission of the H3K27me3 epigenetic mark
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Terpos, E., Ntanasis-Stathopoulos, I., Gavriatopoulou, M., & Dimopoulos, M. A. (2018) · Blood Cancer Journal · doi:10.1038/s41408-017-0037-4 · Cited by 354
Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts
Shupp, A. B., Kolb, A. D., Mukhopadhyay, D., & Bussard, K. M. (2018) · Cancers · doi:10.3390/cancers10060182 · Cited by 155
LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target
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EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications
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Mechanisms of bone destruction in multiple myeloma
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Metadata
- Authors
- Adamik, J., Jin, S., Sun, Q., Zhang, P., Weiss, K. R., Anderson, J. L., Silbermann, R., Roodman, G. D., & Galson, D. L.
- Affiliations
- University of Pittsburgh (US)
- Indiana University Hospital (US)
- Corresponding author
- Roodman, G. David
- Galson, Deborah L.
- Venue
- Molecular Cancer Research
- Published
- 2017-04-01
- Volume
- 15
- Issue
- 4
- Pages
- 405-417
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC5524543
- OpenAlex
- W2582073651
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 9 · 2019: 12 · 2018: 13 · 2017: 6
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- U.S. Department of Veterans Affairs (I01 CX000623)
- National Cancer Institute (K08CA177927, P30CA047904)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059679)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- multiple myeloma, osteogenic differentiation, Runx2, epigenetic repression, EZH2, HDAC1, GFI1, H3K27me3, LSD1, osteolytic lesions, TNF-α, chromatin remodeling, epigenetic therapy
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Differentiation, DNA-Binding Proteins, Humans, Indoles, Multiple Myeloma, Osteoblasts, Promoter Regions, Genetic, Pyridones, Transcription Factors, Coculture Techniques, Epigenesis, Genetic, Cell Line, Tumor, Core Binding Factor Alpha 1 Subunit, Mice, Histone Deacetylase 1, Histone Deacetylase Inhibitors
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