{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333856/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333856"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"EZH1/2 inhibition selectively targets SMARCA4/2 co-deficient lung cancer cells by suppressing stemness and proliferation [ATAC-seq]","description":"SMARCA4-deficient thoracic malignancies comprise biologically heterogeneous tumors, ranging from conventional non-small cell lung cancer with SMARCA4 alterations to thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), an aggressive entity frequently associated with concomitant SMARCA2 loss. However, the extent to which SMARCA4-deficient lung cancer cell lines recapitulate SMARCA4-UT-like biology remains incompletely defined. Here, we characterized lung cancer cell lines across distinct SMARCA4 and SMARCA2 states and identified a subgroup with SMARCA4/2 co-deficiency that exhibited reduced expression of epithelial lineage markers and transcriptional similarity to SMARCA4-UT and other SWI/SNF-deficient malignancies. The EZH1/2 inhibitor HM97662 selectively suppressed growth in SMARCA4/2-deficient cells, with limited effects in SMARCA2-proficient cells. 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.","dates":{"publication":"2026/08/19"},"accession":"GSE333856","cross_references":{"GSM":["GSM9776048","GSM9776049","GSM9776046","GSM9776047","GSM9776044","GSM9776045","GSM9776042","GSM9776043","GSM9776040","GSM9776041","GSM9776050","GSM9776039"],"GPL":["34281"],"GSE":["333856"],"taxon":["Homo sapiens"],"PMID":["[42567102]"]}}