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Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE197781 | GEO | 2022/06/27

REPOSITORIES: GEO

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Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

Project description:In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.

2022-10-14 | PXD032041 | Pride

Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Project description:In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

| S-EPMC7613567 | biostudies-literature

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]

2022-06-27 | GSE197776 | GEO

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue RNA-Seq]

2022-06-27 | GSE197780 | GEO

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Cell line ChIP-Seq]

2022-06-27 | GSE197774 | GEO

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence (ChIP-seq)

Project description:Understanding how prostate cancer cells adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenetic plasticity towards pro-survival signaling, and uncovered circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel clinical lead for therapeutic development.

| EGAS00001006017 | EGA

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence (RNA-seq)

| EGAS00001006016 | EGA

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

Project description:Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

| PRJNA812029 | ENA

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]

Project description:Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]

| PRJNA812023 | ENA

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue RNA-Seq]

Project description:Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue RNA-Seq]

| PRJNA812036 | ENA

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