EZH1/2 inhibition selectively targets SMARCA4/2 co-deficient lung cancer cells by suppressing stemness and proliferation [ATAC-seq]

EZH1/2 inhibition broadly reduced H3K27me3 and induced derepression of PRC2 targets regardless of drug sensitivity. However, its biological effects were most pronounced in SMARCA4/2-deficient cells, where it promoted apoptosis, reduced stemness marker expression, attenuated the SMARCA4-UT-associated transcriptional signature, and suppressed MYC/MAX target and cell-cycle programs. Chromatin accessibility analysis further revealed cell-line-specific patterns of accessibility loss, with reduced accessibility at stemness- and lineage-associated transcription factor motif-enriched regions coupled with transcriptional repression of nearby genes in SMARCA4/2-deficient cells.

These findings support dual EZH1/2 inhibition as a potential therapeutic vulnerability in SMARCA4/2-deficient, SMARCA4-UT-like lung cancer cells.