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ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384902/ https://www.ncbi.nlm.nih.gov/pubmed/34466783 http://dx.doi.org/10.1016/j.isci.2021.102953 |
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author | Pozo, Karine Kollipara, Rahul K. Kelenis, Demetra P. Rodarte, Kathia E. Ullrich, Morgan S. Zhang, Xiaoyang Minna, John D. Johnson, Jane E. |
author_facet | Pozo, Karine Kollipara, Rahul K. Kelenis, Demetra P. Rodarte, Kathia E. Ullrich, Morgan S. Zhang, Xiaoyang Minna, John D. Johnson, Jane E. |
author_sort | Pozo, Karine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8384902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-83849022021-08-30 ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer Pozo, Karine Kollipara, Rahul K. Kelenis, Demetra P. Rodarte, Kathia E. Ullrich, Morgan S. Zhang, Xiaoyang Minna, John D. Johnson, Jane E. iScience Article 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. Elsevier 2021-08-05 /pmc/articles/PMC8384902/ /pubmed/34466783 http://dx.doi.org/10.1016/j.isci.2021.102953 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Pozo, Karine Kollipara, Rahul K. Kelenis, Demetra P. Rodarte, Kathia E. Ullrich, Morgan S. Zhang, Xiaoyang Minna, John D. Johnson, Jane E. ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title | ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title_full | ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title_fullStr | ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title_full_unstemmed | ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title_short | ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer |
title_sort | ascl1, nkx2-1, and prox1 co-regulate subtype-specific genes in small-cell lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384902/ https://www.ncbi.nlm.nih.gov/pubmed/34466783 http://dx.doi.org/10.1016/j.isci.2021.102953 |
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