Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [RNA-Seq]

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that some drug resistant genes were activated during myeloma resistant to bortezomib. Mechanistically, NSD2 can interact with SRC-3, its SET domain is responsible to H3K36me2 to enhance the transcriptional activity of SRC-3 target gene. The inhibitor of SRC-3, SI-2, can impaired the interaction between NSD2 and SRC-3, caused the distribution of H3K36me2 changed on the genome-wide, and inhibit the transcription of those drug resistant genes. Overall design: For myeloma cell, LP-1, we established bortezomib-resistant cell line which IC50 to bortezomib have been augmented over 5 folds, and the anti-apoptotic capacity remarkably enhanced. In this condition, we treated the LP-1 wild-type cell and bortezomib-resistant cell with 25nM SI-2, and cells were harvested for gene expression profiling when SI-2 was treated for 24h. Two replicates were performed.