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BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

ABSTRACT: Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. To investigate what genes are affected by NHWD-870 (a BET inhibitor) in SCLC-N subtype tumors in vivo, we performed an RNA-seq analysis of the tumor cells isolated from the LX22 PDX after NHWD-870 treatment at 2mg/kg via oral gavage daily for five days.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210110 | GEO | 2022/11/23

REPOSITORIES: GEO

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BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The purpose of this part of the study was to investigate what genes are affected by BET inhibitor JQ1 in small cell lung cancer cell line COR-L279 (a SCLC-N subtype).

2022-11-23 | GSE210104 | GEO

BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The goal of this experiment was to characterize the genome-wide binding profiles of BET proteins, RPII, and H3K27Ac upon NEUORD1 knockout in H446 cells.

2022-11-23 | GSE210113 | GEO

BET inhibitors target the SCLC-N subtype of small-cell lung cancer by blocking NEUROD1 transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The goals for this part of the study were: 1) to identify the NEUROD1 target genes in the SCLC-N subtype small cell lung cancer. To this end, we knocked out NEUROD1 in H446 cells (SCLC-N subtype) by CRISPR and assessed gene expression alterations in three knockout and three control clones. An integrated analysis of the RNA-seq data and the NEUROD1 ChIP-seq data was performed to identify the NEUROD1 target genes; 2) to assess how NEUROD1 knockout affects the response to JQ1 (a BET inhibitor).

2022-11-23 | GSE210101 | GEO

BET bromodomain proteins regulate enhancer function during adipogenesis

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Project description:Extensive genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on expression of lineage-defining transcription factors including ASCL1 and NEUROD1, which together account for ~80% of this disease. ASCL1 and NEUROD1 activate SCLC oncogene expression and drive distinct transcriptional programs. ASCL1 is also required for tumorigenesis in SCLC mouse models, and both ASCL1 and NEUROD1 maintain the in vitro growth and oncogenic properties of ASCL1+ or NEUROD1+ SCLC cell lines. Strategies to inhibit ASCL1 and NEUROD1 may therefore represent an attractive, targeted SCLC therapy and provide a tool to investigate the underlying plasticity of the predominant SCLC subtypes. However, ASCL1 and NEUROD1 have long been considered “undruggable” vulnerabilities. Here, we use a proteomic approach to identify Karyopherin β1 (KPNB1) as a nuclear import receptor for ASCL1 and NEUROD1 in SCLC, and demonstrate that the inhibition of KPNB1 using a variety of genetic or pharmacological approaches leads to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacological targeting of KPNB1 preferentially disrupts ASCL1/NEUROD1+ SCLC cell line growth in vitro and ASCL1+ tumor growth in an in vivo patient derived xenograft (PDX) model of SCLC.

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Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (ChIP-seq)

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2016-07-21 | E-GEOD-69394 | biostudies-arrayexpress

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (RNA-seq)

Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors RNA-seq analysis performed on two ASCL1high and two NEUROD1high human SCLC cell lines to identify gene expression patterns in these cells. Also, we performed RNA-seq in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

2016-07-21 | E-GEOD-69393 | biostudies-arrayexpress

ChIP-seq of NeuroD1 and H3K4me3 in SCLC cells

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BET Bromodomain Inhibition Blocks the Function of a Critical AR-Independent Master Regulator Network in Lethal Prostate Cancer

Project description:BET bromodomain inhibitors are known to block prostate cancer cell survival through suppression of c-Myc and androgen receptor (AR) function. However, little is known about other transcriptional modulators whose function is blocked by these drugs and the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency may be increasing. In this study we determined that BET bromodomain inhibition suppresses survival of a diverse set of CRPC cell models, including those that do not express the AR or in which c-Myc is not suppressed. To identify additional transcriptional regulators whose suppression contributes to the anti-tumor effects of BET bromodomain inhibition, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1, measured genome-wide gene expression changes, and then used the Master Regulator Inference Algorithm (MARINa). This approach identified transcriptional regulators whose function is blocked by JQ1 and whose suppression recapitulates the effects of BET bromodomain inhibition. High Expression of these Master Regulators in aggressive human CRPC demonstrates their clinical relevance.

2019-03-20 | GSE98069 | GEO

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [ChIP-Seq]

Project description:Heart failure is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. Coordinate activation of developmental, inflammatory, fibrotic and growth regulators underlies the hallmark phenotypes of pathologic cardiac hypertrophy and contractile failure. While transactivation in this context is known to be associated with recruitment of histone acetyl-transferase enzymes and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in heart failure. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during the evolution of heart failure. BET inhibition suppresses cardiomyocyte hypertrophy in a cell-autonomous manner, confirmed by RNA interference in vitro. Following both pressure overload and neurohormonal stimulation, BET inhibition potently attenuates pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to heart failure pathogenesis. Specifically, BET bromodomain inhibition in mice abrogates pathology-associated pause release and transcriptional elongation, thereby preventing activation of cardiac transcriptional pathways relevant to the gene expression profile of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in heart failure. ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor

2013-08-06 | E-GEOD-46668 | biostudies-arrayexpress

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