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ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

ABSTRACT: 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

ORGANISM(S): Homo sapiens

SUBMITTER: Yang Xie

PROVIDER: E-GEOD-61197 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers.

Augustyn Alexander A Borromeo Mark M Wang Tao T Fujimoto Junya J Shao Chunli C Dospoy Patrick D PD Lee Victoria V Tan Christopher C Sullivan James P JP Larsen Jill E JE Girard Luc L Behrens Carmen C Wistuba Ignacio I II Xie Yang Y Cobb Melanie H MH Gazdar Adi F AF Johnson Jane E JE Minna John D JD

Proceedings of the National Academy of Sciences of the United States of America 20140929 41

Aggressive neuroendocrine lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), represent an understudied tumor subset that accounts for approximately 40,000 new lung cancer cases per year in the United States. No targeted therapy exists for these tumors. We determined that achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary neuroendocrine cells, is essential for the survival of a majority of lung cancers (b ...[more]

PMID: 25267614

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ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

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

2014-10-01 | GSE61197 | GEO

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (ChIP-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 ChIP-seq analysis performed on three ASCL1high and two NEUROD1high human SCLC cell lines to identify ASCL1 and/or NEUROD1 binding sites in these two types of cells. Also, we performed ChIP-seq for Ascl1 binding sites in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

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

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

2023-12-08 | PXD037670 | Pride

Histone ChIP NS5 Ascl1-ERT2

Project description:Here we performed a ChIP-seq experiment on a sample of adherent cultures of mouse neural stem cells (NS5 cell line) expressing an inducible version of the proneural factor Mash1/Ascl1 (Ascl1-ERT2) under normal growth conditions and after 24 hours of activation by 4-Hydroxytamoxifen. This resulted in the generation of a genome-wide map of histone modifications H3K27ac and H3K4me1.

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Project description:To identify the downstream targets of transcription factor Ascl1, transcriptional profiling of rat glial cell line, CG4 cell, transfected with either Ascl1 or mock control was performed. Comparison was performed between Ascl1 overexpressing CG4 cell and mock control transduced cell on 3D-Gene rat mRNA oligo 12k chip. Biological replication was not prepared. The results were confirmed by real time RT-PCR in several genes.

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RNAi knock down of ASCL1 in human NCI-H1618 small cell lung cancer cells

Project description:NCI-H1618 cells treated on d0 and d3 with 25 nM control or ASCL1-targeting siRNA. Biologic triplicate RNA samples harvested at day 5.

2008-11-13 | E-MEXP-1857 | 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

Role of Ascl1 in pancreatic beta cell response to metabolic stress

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