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ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

ABSTRACT: ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

PROVIDER: PRJNA416257 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6233830.fastq.gz	Fastqsanger.gz
	SRR6233831.fastq.gz	Fastqsanger.gz
	SRR6233822.fastq.gz	Fastqsanger.gz
	SRR6233832.fastq.gz	Fastqsanger.gz
	SRR6233823.fastq.gz	Fastqsanger.gz

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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

The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

Project description:Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1Î± and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role of Rb in HIF1-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that Rb regulates specific chromosomal gene clusters and loss of Rb in conjunction with hypoxia leads to dysregulation of HIF1-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. RNAs derived from human LNCaP cells stably infected with either scrambled control shRNA or a shRNA directed to RB1. Cells were exposed to either 24 h hypoxia (1% O2) or maintained under normoxic conditions. Biological triplicates were tested and compared.

2016-02-24 | E-GEOD-78245 | biostudies-arrayexpress

Genome-wide maps of ONECUT2 binding sites in 22Rv1 human castration resistant prostate cancer cell

Project description:In order to determine whether ONECUT2 directly regulates the AR transcriptional program, or whether the effect of ONECUT2 is a mere consequence of AR downregulation, we performed ONECUT2 ChIP-sequencing (ChIP-seq) using the 22Rv1 human castration resistant prostate cancer cell line, which expresses high levels of ONECUT2 in comparison to other human prostate cancer cell lines

2018-10-26 | GSE97551 | GEO

The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

Project description:Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role of Rb in HIF1-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that Rb regulates specific chromosomal gene clusters and loss of Rb in conjunction with hypoxia leads to dysregulation of HIF1-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.

2016-02-24 | GSE78245 | GEO

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (RNA-seq)

Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. 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.

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ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (ATAC-seq)

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ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (CUT&RUN-seq)

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Neuroendocrine prostate cancer models

Project description:Neuroendocrine prostate cancer models

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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.

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MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

Project description:MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

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