ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer
Summary: 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 patien...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221009214 |
| _version_ | 1818909896530198528 |
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| author | Karine Pozo Rahul K. Kollipara Demetra P. Kelenis Kathia E. Rodarte Morgan S. Ullrich Xiaoyang Zhang John D. Minna Jane E. Johnson |
| author_facet | Karine Pozo Rahul K. Kollipara Demetra P. Kelenis Kathia E. Rodarte Morgan S. Ullrich Xiaoyang Zhang John D. Minna Jane E. Johnson |
| author_sort | Karine Pozo |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-19T22:34:12Z |
| format | Article |
| id | doaj.art-6101dd2d24d74964a5a6b60cca305401 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-19T22:34:12Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-6101dd2d24d74964a5a6b60cca3054012022-12-21T20:03:16ZengElsevieriScience2589-00422021-09-01249102953ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancerKarine Pozo0Rahul K. Kollipara1Demetra P. Kelenis2Kathia E. Rodarte3Morgan S. Ullrich4Xiaoyang Zhang5John D. Minna6Jane E. Johnson7Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USAMcDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USADepartment of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004221009214molecular biologybioinformaticscancer systems biology |
| spellingShingle | Karine Pozo Rahul K. Kollipara Demetra P. Kelenis Kathia E. Rodarte Morgan S. Ullrich Xiaoyang Zhang John D. Minna Jane E. Johnson ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer iScience molecular biology bioinformatics cancer systems biology |
| 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 | molecular biology bioinformatics cancer systems biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221009214 |
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