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Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152231 | GEO | 2021/03/11

REPOSITORIES: GEO

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Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.

Project description:The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP-seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC-Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.

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Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases [RNA-seq]

Project description:We performed transcriptional profiling and chromatin immunoprecipitation for the key oncogenic driver in prostate cancer, Androgen Receptor (AR) and FOXA1, H3K27ac, H3K27me3 and CTCF to chart the epigenomic landscape in four clonal metastatic tumors from a single prostate cancer patient whose clinical course was closely followed over 17 years. The vast majority (~80% ) of all AR binding sites were shared among all samples and found in normal prostate tissue and primary prostate cancers signifying core binding events within the prostate lineage. Remarkably, active (H3K27ac marked) metastatic sample-specific AR binding sites showed no differential transcriptional output, indicating a robustness of transcriptional programming across different metastases samples.

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Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases

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Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases [RNA-seq]

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A core program of gene expression characterizes cancer metastases.

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N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer.

Project description:The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

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