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| Status |
Public on Sep 21, 2021 |
| Title |
Potent androgen receptor inhibition unleashes oncogenic action of the KLF5 stem cell transcription factor in castration-resistant prostate cancer [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Advanced prostate cancer (PC) can be treated with endocrine therapies that inhibit transcriptional activity of the androgen receptor (AR). However, PC will ultimately evolve under the selection pressure of these therapies and progress to a lethal phenotype termed castration-resistant PC (CRPC). Recent studies suggest that de-differentiation away from an AR-driven luminal cell identity may be a key, early step. However, early therapy-induced mechanisms of prostate cancer cell de-differentiation are poorly understood. Here we show that the stem cell transcription factor Kruppel-like factor 5 (KLF5) is transcriptionally repressed by AR, and de-repressed by enzalutamide. KLF5 expression is high in a subset of CRPC tissues, but low in primary adenocarcinoma. KLF5 functioned as oncogene in CPRC cells, promoting cellular migration, anchorage-independent growth, expression of basal cell markers, and transcriptional signatures of CRPC lineage plasticity, but had modest effects on cell proliferation. Chromatin immuno-precipitation (ChIP)-sequencing, RNA-sequencing, and co-immunoprecipitation experiments established a physical interaction between KLF5 and AR, and integrative analysis revealed that KLF5 and AR drive opposing transcriptional programs. We identified ERBB2 as a point of transcriptional convergence that was activated by KLF5 and repressed by AR. Accordingly, KLF5 expression levels in CRPC tissues correlated with predicted sensitivity to the dual EGFR inhibitor lapatanib, and the ERBB2-specific inhibitor mubritinib blocked KLF5-driven cell migration. Collectively, these findings implicate KLF5 as an AR-suppressed oncogene that drives early steps in CRPC de-differentiation and disease progression.
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| Overall design |
RNA-seq analysis of the prostate cancer cell line R1-AD1 infected with lentivirus encoding control shRNA (shCon) or two independent shRNAs targeting KLF5 (shKLF5), cultured in medium supplemented with 10% charcoal-stripped serum (CSS) and stimulated 24h with 1 nM DHT or 0.1% (v/v) ethanol as vehicle control. RNA-seq analysis was also performed with AR gene-engineered R1-D567 prostate cancer cells infected with lentivirus encoding shCon or shKLF5, cultured in medium supplemented with 10% CSS.
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| Contributor(s) |
Dehm S, Che M, Munro S |
| Citation(s) |
34737261 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA174777 |
AR gene rearrangements and AR signaling in prostate cancer |
UNIVERSITY OF MINNESOTA |
Scott M Dehm |
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| |
| Submission date |
Apr 16, 2020 |
| Last update date |
Dec 29, 2021 |
| Contact name |
Scott Dehm |
| E-mail(s) |
[email protected]
|
| Organization name |
Masonic Cancer Center, University of Minnesota
|
| Street address |
Mayo Mail Code 806, 420 Delaware St SE
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| City |
Minneapolis |
| ZIP/Postal code |
55455 |
| Country |
USA |
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| Platforms (1) |
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| Samples (27)
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| This SubSeries is part of SuperSeries: |
| GSE148808 |
Potent androgen receptor inhibition unleashes oncogenic action of the KLF5 stem cell transcription factor in castration-resistant prostate cancer |
|
| Relations |
| BioProject |
PRJNA625789 |
| SRA |
SRP256723 |
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