Inactivation of the histone H3 K36 methyltransferase NSD1 confers resistance to EZH2 inhibition [RNA-Seq]

Disruption of antagonism between SWI/SNF chromatin remodelers and Polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of Polycomb protein EZH2 was approved for treatment of sarcomas mutant in SWI/SNF subunit SMARCB1, but resistance occurs. Here we sought to identify additional contributors to SWI/SNF-Polycomb antagonism and potential resistance mechanisms. We performed CRISPR screens and found that NSD1 loss caused resistance to EZH2 inhibition. NSD1 loss reduced H3K36me2 and impaired transcriptional activation of targets inhibited by EZH2 or activated by SMARCB1. Further, inhibiting the H3K36me2 demethylase KDM2A restored EZH2 inhibition in cells lacking NSD1. Our results expand the mechanistic understanding of SWI/SNF and Polycomb interplay and identify NSD1 as key for coordinating this transcriptional control. To investigate how loss of NSD1 affects SWI/SNF mediated control of gene expression, we induced SMARCB1 in the presence and absence of NSD1 and RNA sequencing (RNA-seq) after 24 hours. Furthermore, to study whether NSD1 is essential for the transcriptional activation that occurs following loss of EZH2-mediated silencing, we performed RNA-seq of G401 control (shCTRL) and NSD1 knockdown (shNSD1) cells treated with DMSO or GSK126 for 72 hours.