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• W2492491922 abstract "Abstract Introduction Multiple myeloma (MM) is a clonal malignancy of plasma cells that frequently causes skeleton destruction. The osteolytic lesions rarely heal even in those patients who are in long-term remission. In MM bone disease, differentiation of osteoblasts is suppressed due to the down-regulation of the Runx2 gene, a master osteoblast differentiation transcription factor. Growth independent factor 1 (Gfi1) is a 55 kDa protein that contains an N-terminal SNAG domain and 6 zinc finger domains at the C-terminus. It is a transcription factor that can recruit chromatin modifiers to genes. We reported that MM cells induce expression of Gfi1 in bone marrow stromal cells, and that Gfi1 directly represses the Runx2 gene. Our previous data indicated that a histone deacetylases (HDAC) inhibitor, Trichostatin A, could block Gfi1-mediated Runx2 promoter repression. However, how Gfi1 activity is modulated by HDAC inhibitors and whether Gfi1 acetylation is involved in the HDAC inhibitor prevention of Runx2 repression are unknown. Therefore, we investigated if Gfi1 is acetylated and if the activity of Gfi1 is regulated by its acetylation status. We also examined the MM-induced changes in Gfi1 and HDACs occupancy on the Runx2 gene. Methods Full length or truncated Gfi1 cDNA constructs were used to express Gfi1 protein by transient transfections. After immunoprecipitation of Gfi1, the acetylation status of Gfi1 was determined by anti-acetylated lysine antibody using western blotting. Overexpression or knockdown of lysine acetyltransferase p300 was done by co-transfection of p300 cDNA or shRNA plasmids. Trichostatin A (5 µM) and nicotinamide (10 mM) were used to inhibit the activity of HDACs. Site-directed mutagenesis was used to change Gfi1 residue lysine 292 to arginine (Gfi1-K292R). For luciferase reporter assays, the pGL4.10 vector constructed with a mouse Runx2 promoter region (-976 ∼ +111) was transfected into mouse pre-osteoblast cell line MC-4. A biotinylated double-stranded oligonucleotide spanning the Gfi1 binding region (-40 ∼ -1) in the mouse Runx2 promoter was utilized for oligonucleotide pull-down assays. Chromatin immunoprecipitation (ChIP) was used to characterize the MM-induced changes in the Runx2 gene chromatin. Results We found that Gfi1 was a target of acetylation and that p300 was co-localized and co-immunoprecipitated with Gfi1. Interestingly, the deacetylation of Gfi1 was controlled by both Zn2+ and NAD+ dependent deacetylases. Using different truncated Gfi1 cDNA constructs, we identified lysine 292 in Gfi1 zinc finger 2 as a critical site for acetylation. Mutant Gfi1-K292R displayed significant resistance to acetylation in the presence of HDAC inhibitors, confirming that Gfi1-K292 is the major acetylation site. Importantly, oligonucleotide pull down assays showed that Gfi1-K292R exhibited stronger DNA binding activity than Gfi1-WT to the Gfi1 binding site in the Runx2 promoter. In luciferase assays, increasing or decreasing lysine acetyltransferase activity by overexpression or knockdown of p300 resulted in the attenuation or enhancement in Gfi1 repression of the Runx2 promoter, respectively. Further, the acetylation-resistant Gfi1-K292R more strongly repressed the Runx2 promoter, which was not rescued by HDAC inhibitors, indicating that the contribution of HDAC inhibitors to increased acetylated Gfi1 is a major mechanism for prevention of Gfi1-mediated Runx2 repression. Lastly, ChIP analysis of the Runx2 gene in MC-4 cells before and after co-culture with myeloma cells revealed that increased Gfi1 occupancy at the Runx2 gene correlated with increased HDAC1 and decreased Pol-II and H3K9ac, confirming that the interaction between Gfi1 and HDACs is involved in the repression of the Runx2 gene. Conclusions Taken together, our results indicate that Gfi1 is an acetylated protein and suggest that increasing acetylation of Gfi1represents a potential therapeutic target for reversing Gfi1-mediated Runx2 repression and promoting osteoblast differentiation in MM bone disease. Disclosures: Roodman: Amgen: Membership on an entity’s Board of Directors or advisory committees; Eli Lilly: Research Funding." @default.
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• W2492491922 date "2013-11-15" @default.
• W2492491922 modified "2023-10-01" @default.
• W2492491922 title "Increase of Gfi1 Acetylation by HDAC Inhibitors Blocks Gfi1-Mediated Runx2 Repression in Osteoblast Precursors in Multiple Myeloma Bone Disease" @default.
• W2492491922 doi "https://doi.org/10.1182/blood.v122.21.753.753" @default.
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