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| Status |
Public on Jan 12, 2023 |
| Title |
SMAD3 promotes the expression and activity of androgen receptor in prostate cancer [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNAseq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ~50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for pLKO.1, sh-SMAD3, sh-SMAD2, sh-SMAD4 in RV1 cells
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| Contributor(s) |
Qi J, Jeon H |
| Citation(s) |
36727462 |
| |
| Submission date |
Aug 24, 2022 |
| Last update date |
Apr 13, 2023 |
| Contact name |
Jianfei Qi |
| E-mail(s) |
JQi@som.umaryland.edu
|
| Phone |
4107060734
|
| Organization name |
University of Maryland
|
| Department |
Biochemistry and Molecular Biology
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| Lab |
Qi lab
|
| Street address |
655W baltimore street
|
| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21201 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE211946 |
SMAD3 promotes the expression and activity of androgen receptor in prostate cancer. |
|
| Relations |
| BioProject |
PRJNA873038 |
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