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| Status |
Public on Jun 27, 2022 |
| Title |
Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA-seq data for primary prostate carcinomas before and after neoadjuvant enzalutamide therapy. The raw sequencing data cannot be stored with GEO due to patient privacy and was uploaded to the European Genome/Phenome Archive (EGAS00001006016).
For tissue ChIP-seq and RNA-seq, the raw sequencing data cannot be stored with GEO due to patient privacy and had to be uploaded to the European Genome/Phenome Archive (ChIP-seq: EGAS00001006017, RNA-seq: EGAS00001006016).
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| Contributor(s) |
Zwart W, Linder S, Hoogstraat M, Bergman A |
| Citation(s) |
35754340 |
| |
| Submission date |
Mar 02, 2022 |
| Last update date |
Jun 29, 2022 |
| Contact name |
Wilbert Zwart |
| E-mail(s) |
w.zwart@nki.nl
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| Organization name |
Netherlands Cancer Institute
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| Department |
Oncogenomics
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| Street address |
Plesmanlaan 121
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| City |
Amsterdam |
| ZIP/Postal code |
1066 CX |
| Country |
Netherlands |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (94)
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| This SubSeries is part of SuperSeries: |
| GSE197781 |
Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence |
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| Relations |
| BioProject |
PRJNA812036 |
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