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SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [ChIP-seq]

GSE256346 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 5 samples Submitted 2024/08/28 Platform GPL24676
Summary
Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, suppressing NE programs. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST splicing. The SMARCA2/4 inhibitor FHD-286 induces loss of NE features and drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.
Published in
SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing
Redin E, Sridhar H, Zhan YA et al. · Journal of hematology & oncology 2024 · PMID 39080761 · doi:10.1186/s13045-024-01572-3
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Also filed as BioProject PRJNA1079238 and SRA study SRP490989. Searching any of these in the dataset finder brings you back here.

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