ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer
Abstract Background Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making...
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doaj-0475ba2f017c4860a227d291914864942020-11-25T03:11:58ZengBMCGenome Medicine1756-994X2020-07-0112112010.1186/s13073-020-00760-3ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancerAileen Patricia Szczepanski0Zibo Zhao1Tori Sosnowski2Young Ah Goo3Elizabeth Thomas Bartom4Lu Wang5Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of MedicineSimpson Querrey Center for Epigenetics, Northwestern University Feinberg School of MedicineProteomics Center of Excellence, Northwestern UniversitySimpson Querrey Center for Epigenetics, Northwestern University Feinberg School of MedicineSimpson Querrey Center for Epigenetics, Northwestern University Feinberg School of MedicineSimpson Querrey Center for Epigenetics, Northwestern University Feinberg School of MedicineAbstract Background Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making it difficult to develop both screenings and effective treatments. In this study, we examine a novel mechanistic insight in SCLC cells that could potentially provide a more sensitive therapeutic alternative for SCLC patients. Methods Biochemistry studies, including size exclusion chromatography, mass spectrometry, and western blot analysis, were conducted to determine the protein-protein interaction between additional sex combs-like protein 3 (ASXL3) and bromodomain-containing protein 4 (BRD4). Genomic studies, including chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and genome-wide analysis, were performed in both human and mouse SCLC cells to determine the dynamic relationship between BRD4/ASXL3/BAP1 epigenetic axis in chromatin binding and its effects on transcriptional activity. Results We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4’s extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. Genetic depletion of ASXL3 results in a genome-wide reduction of histone H3K27Ac levels and BRD4-dependent gene expression in SCLC. Pharmacologically induced inhibition with BET-specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC that is characterized with high expression of ASXL3. Conclusions Collectively, this study provides a mechanistic insight into the oncogenic function of BRD4/ASXL3/BAP1 epigenetic axis at active chromatin enhancers in SCLC-A subtype, as well as a potential new therapeutic option that could become more effective in treating SCLC patients with a biomarker of ASXL3-highly expressed SCLC cells.http://link.springer.com/article/10.1186/s13073-020-00760-3ASXL3BAP1 complexBRD4SCLCEnhancer activityBET inhibitors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aileen Patricia Szczepanski Zibo Zhao Tori Sosnowski Young Ah Goo Elizabeth Thomas Bartom Lu Wang |
spellingShingle |
Aileen Patricia Szczepanski Zibo Zhao Tori Sosnowski Young Ah Goo Elizabeth Thomas Bartom Lu Wang ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer Genome Medicine ASXL3 BAP1 complex BRD4 SCLC Enhancer activity BET inhibitors |
author_facet |
Aileen Patricia Szczepanski Zibo Zhao Tori Sosnowski Young Ah Goo Elizabeth Thomas Bartom Lu Wang |
author_sort |
Aileen Patricia Szczepanski |
title |
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer |
title_short |
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer |
title_full |
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer |
title_fullStr |
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer |
title_full_unstemmed |
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer |
title_sort |
asxl3 bridges brd4 to bap1 complex and governs enhancer activity in small cell lung cancer |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2020-07-01 |
description |
Abstract Background Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making it difficult to develop both screenings and effective treatments. In this study, we examine a novel mechanistic insight in SCLC cells that could potentially provide a more sensitive therapeutic alternative for SCLC patients. Methods Biochemistry studies, including size exclusion chromatography, mass spectrometry, and western blot analysis, were conducted to determine the protein-protein interaction between additional sex combs-like protein 3 (ASXL3) and bromodomain-containing protein 4 (BRD4). Genomic studies, including chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and genome-wide analysis, were performed in both human and mouse SCLC cells to determine the dynamic relationship between BRD4/ASXL3/BAP1 epigenetic axis in chromatin binding and its effects on transcriptional activity. Results We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4’s extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. Genetic depletion of ASXL3 results in a genome-wide reduction of histone H3K27Ac levels and BRD4-dependent gene expression in SCLC. Pharmacologically induced inhibition with BET-specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC that is characterized with high expression of ASXL3. Conclusions Collectively, this study provides a mechanistic insight into the oncogenic function of BRD4/ASXL3/BAP1 epigenetic axis at active chromatin enhancers in SCLC-A subtype, as well as a potential new therapeutic option that could become more effective in treating SCLC patients with a biomarker of ASXL3-highly expressed SCLC cells. |
topic |
ASXL3 BAP1 complex BRD4 SCLC Enhancer activity BET inhibitors |
url |
http://link.springer.com/article/10.1186/s13073-020-00760-3 |
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