Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pozo, Karine, Kollipara, Rahul K., Kelenis, Demetra P., Rodarte, Kathia E., Ullrich, Morgan S., Zhang, Xiaoyang, Minna, John D., Johnson, Jane E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
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
_version_ 1783741993272213504
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
work_keys_str_mv AT pozokarine ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT kollipararahulk ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT kelenisdemetrap ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT rodartekathiae ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT ullrichmorgans ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT zhangxiaoyang ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT minnajohnd ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer
AT johnsonjanee ascl1nkx21andprox1coregulatesubtypespecificgenesinsmallcelllungcancer