Therapeutic targeting of BAP1/ASXL3 sub-complex in ASCL1-dependent small cell lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA789774 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17256700.fastq.gz | Fastqsanger.gz | |||
| SRR17256701.fastq.gz | Fastqsanger.gz | |||
| SRR17256676.fastq.gz | Fastqsanger.gz | |||
| SRR17256677.fastq.gz | Fastqsanger.gz | |||
| SRR17256678.fastq.gz | Fastqsanger.gz |
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Project description:Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1’s catalytic activity dramatically disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II dramatically inhibits SCLC cell viability and tumor growth in vivo via repression of neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in cells.
2022-02-23 | GSE191106 | GEO
Project description:Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1's catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II represses neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and dramatically inhibits SCLC cell viability and tumor growth in vivo. In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1's activity as a novel SCLC therapy.
| S-EPMC8993689 | biostudies-literature
Project description:The bromodomain and extra-terminal (BET) protein BRD4 functions as a transcriptional activator and is a therapeutic target for different human cancers. Here, we report a critical link between Polycomb repressive deubiquitinase-BAP1 (PR-DUB) complex and BRD4, which is bridged by the physical interaction between additional sex combs-like protein 3 (ASXL3) in small cell lung cancer (SCLC). We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4-extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 at active enhancers. Genetic depletion of ASXL3 leads to a genome-wide reduction of histone H3K27Ac levels as well as BRD4 occupancy, resulting in a similar change of gene expression profile induced by BET inhibitors. Pharmacologically-induced inhibition with BET specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC, characterized with high expression of ASXL3. Collectively, this study provides mechanistic insight into the oncogenic function of ASXL3-BRD4 axis in SCLC.
2020-06-24 | GSE145028 | GEO
Project description:ChIP-Seq analysis performed on 5 ASCL1(+) cell lines and 2 ASCL1 (-) cell lines in order to understand the transcriptome of ASCL1 as it pertains to high-grade neuroendocrine lung cancers 5 ASCL1(+) lung cancer cell lines and 2 ASCL1(-) lung cancer cell lines were compared using ChIP-Seq analysis
2014-10-01 | E-GEOD-61197 | biostudies-arrayexpress
Project description:The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.
2022-09-15 | GSE196860 | GEO
Project description:The deubiquitinase BAP1 is a candidate tumor suppressor regulating cell proliferation in human and is required for development in Drosophila. BAP1 is assembled into high molecular weight transcriptional multi-protein complexes. In order to identify potential BAP1 target genes, global mRNA expression profiling using microarrays was conducted. U2OS cells, transfected with a non-target control shRNA or shRNAs targeting BAP1, were selected with puromycin containing medium and then synchronized at the G1/S border to allow comparative analysis of gene expression.
2010-11-05 | E-GEOD-23035 | biostudies-arrayexpress
Project description:We report the genome wide binding sites of BAP1, HCF1 and OGT in bone marrow derived macrophages. De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor–1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans. For BAP1, bone marrow derived macrophages were used differentiated from bone marrow cells of BAP1-3X Flag Tagged KI mice we generated. For OGT and HCF1, bone marrow derived macrophages were used from BAP1 WT mice.
2012-11-07 | E-GEOD-40723 | biostudies-arrayexpress
Project description:RNA-seq of UPMM3 with restoration of BAP1 and BAP1 mutant proteins. Cell line UPMM3 contains a frameshift mutation in BAP1.
2018-01-31 | GSE97224 | GEO
Project description:Analysis of the effect that reduced BAP1 levels have on global gene expression.The hypothesis tested was that reduction in BAP1 levels would produce changes in gene expression similar to changes observed in class 2 uveal melanomas. Data provided insight into genes that are disrupted with reduced BAP1 levels. Total RNA was isolated from 92.1 cells transfected with either control or BAP1 knockdown constructs for global expression analysis.
2011-01-06 | E-GEOD-24896 | biostudies-arrayexpress
Project description:BAP1 has been studied as a tumor suppressor. Our aim was to characterize genes that were altered in various hematopoietic cell types upon deletion of BAP1. BAP1 WT versus KO cells.
2012-11-07 | E-GEOD-40541 | biostudies-arrayexpress