Fig. 6: SRC-3 inhibitor SI-2 abolishes NSD2/SRC-3 interaction and sensitizes BTZ treatment in myeloma cells.

a Cleavage of PARP as the marker of apoptosis in MM cell treated with bortezomib (BTZ) (0–20 nM) in the presence or absence of 25 nM SI-2 for 24 h (n = 3 biologically independent experiments). b Levels of SRC-3, NSD2, H3K36me2 in wild type (WT) and bortezomib (BTZ)-resistant (BR) myeloma cells treated with 25 nM of SI-2 for 24 h (n = 3 biologically independent experiments). c Co-IP assay shows interaction between SRC-3 and NSD2 in myeloma cells treated with 25 nM SI-2 for 16 h (n = 3 biologically independent experiments). Input, 2% whole cell lysate. IP, anti-SRC-3 antibody. d Degradation rate of SRC-3 protein in myeloma cells stably expressing NSD2 treated with 20 μM cycloheximide (CHX) for up to 10 h with or without 25 nM SI-2 (n = 3 biologically independent experiments). e Confocal immunofluorescence for endogenous SRC-3 droplet foci in bortezomib (BTZ)-resistant (BR) myeloma cells treated with 25 nM SI-2 or vehicle for 24 h (n = 3 biologically independent experiments). Scale bar, 5 μm. f Alteration of IC₅₀ to bortezomib (BTZ) treatment in LP-1 SRC-3-KD cells treated with 25 nM SI-2 or vehicle for 24 h in the presence of SRC-3 full length (FL) or IDR region depletion truncation (ΔIDR) (n = 3 biologically independent experiments). g Heat map for drug resistance responsible genes alteration in 25 nM SI-2 or vehicle-treated bortezomib (BTZ)-resistant (BR) myeloma cells (n = 2 biologically independent experiments). h ChIP-seq profile for 3 clusters of genes enriched by H3K36me2 in bortezomib (BTZ)-resistant (BR) LP-1 cells treated with DMSO or 25 nM of SI-2 (n = 3 biologically independent experiments). Pie chart, percentage of 3 clusters of genes enriched by H3K36me2 in two groups; Density plots, changes of H3K36me2 density around the transcription start site (TSS) region of genes in 3 clusters. i qPCR shows the selected gene expressions in bortezomib (BTZ)-resistant (BR) myeloma cells treated with 25 nM SI-2 for 24 h. (n = 3 biologically independent experiments). Two-sided P-values were determined by Student’s t test; mean ± s.d. Source data are provided as a Source Data file.