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ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer.

ABSTRACT: ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer.

PROVIDER: PRJNA1177381 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31102374_1.fastq.gz	Fastqsanger.gz
	SRR31102374_2.fastq.gz	Fastqsanger.gz
	SRR31102375_1.fastq.gz	Fastqsanger.gz
	SRR31102375_2.fastq.gz	Fastqsanger.gz
	SRR31102376_1.fastq.gz	Fastqsanger.gz

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ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [DMS53]

Project description:ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [DMS53]

| PRJNA1177391 | ENA

ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [NCI-H510A]

Project description:ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [NCI-H510A]

| PRJNA1177392 | ENA

ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [DMS53]

Project description:Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and NOTCH signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small-molecule inhibitor that acts synergically with cisplatin, providing a novel therapeutic strategy for OC2 active SCLC tumors.

2025-05-27 | GSE280217 | GEO

ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer [NCI-H510A]

2025-05-27 | GSE280218 | GEO

ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

Project description:ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

| PRJNA416257 | ENA

ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer.

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-26 | GSE280219 | GEO

ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

Project description:To determine the underlying mechanism of ONECUT2 in prostate cancer hypoxia, we conducted a series of RNA-Seq and ChIP-Seq experiments in LNCaP and PC3 cells under normoxia and hypoxia conditions. We did RNA-Seq in LNCaP cells with or without OC2 overexpression and in PC3 cells with or without OC2 knockdown. We used anti-Flag antibody to perform the ChIP-Seq experiment in PC3 cells with Flag and OC2 fusion protein overexpression. We also performed HIF1A ChIP-Seq in AR-negative prostate cancer cell line PC3 under hypoxia condition with or without ONECUT2 or SMAD3 siRNA knockdown. SMAD3 and HIF2A ChIP-Seq were conducted in PC3 cells under hypoxia condition. To confirm the interactions between transcription factors, we also performed ChIP-reChIP-seq. We did the primary ChIP experiment using anti-SMAD3 antibody and then we subjected the ChIPed chromatin by the primary ChIP to reChIP experiments using anti-HIF1A or anti-HIF2A antibody. The reChIPed DNA was submitted to next generation sequencing.

2019-02-27 | GSE106305 | GEO

ONECUT2 acts a lineage plasticity driver

Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

2024-08-10 | PXD050634 | Pride

A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs [ChIP-seq]

Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.

2022-02-07 | GSE171918 | GEO

A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs [ATAC-seq]

2022-02-07 | GSE171917 | GEO