EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation
| Autor: | Deborah L. Galson, Quanhong Sun, Kurt R. Weiss, Shunqian Jin, G. David Roodman, Judith L. Anderson, Juraj Adamik, Rebecca Silbermann, Peng Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Cancer Research Indoles Pyridones Cellular differentiation Core Binding Factor Alpha 1 Subunit Histone Deacetylase 1 Article Epigenesis Genetic 03 medical and health sciences Mice 0302 clinical medicine stomatognathic system Cell Line Tumor medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Promoter Regions Genetic Molecular Biology Transcription factor Osteoblasts biology EZH2 Osteoblast Cell Differentiation Coculture Techniques Chromatin RUNX2 DNA-Binding Proteins Histone Deacetylase Inhibitors 030104 developmental biology Histone medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis embryonic structures biology.protein Cancer research Multiple Myeloma Chromatin immunoprecipitation Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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