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

doi:10.1016/j.isci.2021.102953

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

iScience. 2021 Aug 5;24(9):102953. doi: 10.1016/j.isci.2021.102953. eCollection 2021 Sep 24.

Authors

Karine Pozo^{1

2}, Rahul K Kollipara³, Demetra P Kelenis¹, Kathia E Rodarte¹, Morgan S Ullrich¹, Xiaoyang Zhang⁴, John D Minna^{2

5

6

7}, Jane E Johnson^{1

6

7}

Affiliations

¹ Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
² Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
³ McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁵ Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

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.

Keywords: bioinformatics; cancer systems biology; molecular biology.