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| Status |
Public on Mar 30, 2022 |
| Title |
ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and divergent differentiation toward neuroendocrine lineage. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identified motifs for the proneuronal transcription factor ASCL1 to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPI governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse the neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.
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| |
|
| Overall design |
ChIP-seq for AR, PRC2 subunits, and the histone marks H3K27Me3 and H3K27Ac, ATAC-seq for measuring chromatin accessibility, and RNA-seq for transcriptome profiling.
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| |
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| Contributor(s) |
Nouruzi S, Ganguli D, Tabrizian N, Kobelev M, Sivak O, Namekawa T, Aguda A, Thaper D, Davies A, Zoubeidi A |
| Citation(s) |
35477723 |
| |
| Submission date |
Sep 01, 2021 |
| Last update date |
May 05, 2022 |
| Contact name |
Amina Zoubeidi |
| E-mail(s) |
azoubeidi@prostatecentre.com
|
| Organization name |
Vancouver Prostate Centre
|
| Street address |
2660 Oak Street
|
| City |
Vancouver |
| State/province |
BC |
| ZIP/Postal code |
V6H 3Z6 |
| Country |
Canada |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE183200 |
ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer |
|
| Relations |
| BioProject |
PRJNA759603 |
| SRA |
SRP335217 |
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