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| Status |
Public on Feb 09, 2024 |
| Title |
Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer [CUTnRUN] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation.
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| Overall design |
CUT&RUN was performed in reprogrammed C4-2B cells for ASCL1, H3K4me3, H3K4me1, H3K27Ac. Experiments performed in triplicates with an IgG control.
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| Contributor(s) |
Li S, Song K, Sun H, Lee JK |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Feb 10, 2023 |
| Last update date |
Feb 09, 2024 |
| Contact name |
John K Lee |
| E-mail(s) |
[email protected]
|
| Phone |
206-667-6819
|
| Organization name |
Fred Hutch Cancer Research
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| Department |
Human Biology Division
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| Lab |
Lee lab
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| Street address |
1100 Fairview Ave N, E2-112
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
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| Platforms (1) |
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| Samples (92)
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| This SubSeries is part of SuperSeries: |
| GSE225026 |
Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer |
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| Relations |
| BioProject |
PRJNA933563 |
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