文章基本信息

标题：ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer
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作者：Karine Pozo ; Rahul K. Kollipara ; Demetra P. Kelenis 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：9
页码：1-24
DOI：10.1016/j.isci.2021.102953
语种：English
出版社：Elsevier
摘要：SummaryLineage-defining transcription factors (LTFs) play key roles in small-cell lung cancer (SCLC) pathophysiology. Delineating the LTF-regulated genes operative in SCLC could provide a road map to identify SCLC dependencies. We integrated chromatin landscape and transcriptome analyses of patient-derived SCLC preclinical models to identify super-enhancers (SEs) and their associated genes in the ASCL1-, NEUROD1-, and POU2F3-high SCLC subtypes. We find SE signatures predict LTF-based classification of SCLC, and the SE-associated genes are enriched with those defined as common essential genes in DepMap. In addition, in ASCL1-high SCLC, we show ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes. Depletion of ASCL1 demonstrates it is a key dependency factor in preclinical SCLC models and directly regulates multiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.Graphical abstractDisplay OmittedHighlights•Super-enhancers support lineage-defining transcription factor SCLC classification•SCLC super-enhancer-associated genes represent essential and lineage-identity genes•ASCL1, NKX2-1, and PROX1 proteins interact in a complex in SCLC-A•ASCL1, NKX2-1, and PROX1 regulate Notch-signaling, NE-specific, and cell-cycle genesMolecular biology; Bioinformatics; Cancer systems biology