ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer

Karine Pozo, Rahul K. Kollipara, Demetra P. Kelenis, Kathia E. Rodarte, Morgan S. Ullrich, Xiaoyang Zhang, John D. Minna, Jane E. Johnson

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Lineage-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.

Original languageEnglish (US)
Article number102953
JournaliScience
Volume24
Issue number9
DOIs
StatePublished - Sep 24 2021

Keywords

  • bioinformatics
  • cancer systems biology
  • molecular biology

ASJC Scopus subject areas

  • General

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