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Fig. 7 | Journal of Experimental & Clinical Cancer Research

Fig. 7

From: SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma

Fig. 7

SUMOylation inhibition decreased c-Myc protein level through regulating protein stability. A TAK-981 treatment decreases c-Myc levels in both MM1S and MM1R cell lines and Dex has no effect on c-Myc level in MM1R cell line. MM1S and MM1R cells were treated with TAK-981 or Dex or both for 48 h, c-Myc and cleaved PAPR (c-PARP) levels were determined by western blot. SUMO-2,3 was blotted to determine global SUMOylation and GAPDH was used as loading control. B GSEA analysis of RNA-seq data shows TAK-981 treatment inhibits c-Myc target gene sets in MM1S and MM1R cells. C TAK-981 treatment decreases c-Myc protein level in time-dependent manner. MM1R cells were treated with TAK-981 at 0.1 μM and cells were harvested at indicated time points. C-Myc protein level was determined by western blot. D TAK-981 treatment accelerates c-Myc protein degradation. MM1R cell pre-treated with vehicle or TAK-981 for 2 h were exposed to cycloheximide (CHX) to block protein synthesis, cells were harvested at indicated time points and analyzed for c-Myc level by western blot. c-Myc level was quantified by ImageJ, normalized to GAPDH and plotted. E SUMO modification of c-Myc was reduced upon TAK-981 treatment. 293 T cells were transfected with His-tagged SUMO-1, His-tagged SUMO-2 and untagged c-Myc expression plasmids. Cells were treated with 0.1 μM TAK-981(TAK) or Vehicle (Veh) for 8 h. Cell lysates were incubated with Ni-NTA beads to pull down all His-tagged SUMO-1 and SUMO-2, followed by Western blot analysis with c-Myc antibody (left) or an anti-His-tag antibody (right). Cells transfected with His-tagged SUMO-1 and SUMO-2 but without c-Myc expressing plasmid were used as control (Ctrl). SUMO-modified and unmodified c-Myc were pointed. F Schematic showing the mechanism of SUMOylation inhibition enhance MM sensitivity to Dex. SUMOylation inhibition decreases c-Myc level, causes reduction of miR-130b, miR-551b and miR-25. The decrease of miR-130b results in induction of GR expression. miR-551b and miR-25 reduction causes increase of TTP, ULK1, p27, resulting in dysregulation of cell cycle, apoptosis and autophagy. All these contribute to enhanced sensitivity to Dex

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