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

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.

• Authors: Karine Pozo, Rahul K Kollipara, Demetra P Kelenis, Kathia E Rodarte, Morgan S Ullrich, Xiaoyang Zhang, John D Minna, Jane E Johnson
• Journal: iScience (iScience) Vol. 24 Issue 9 Pg. 102953 (Sep 24 2021) ISSN: 2589-0042 [Electronic] United States
• PMID: 34466783 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors.