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| Status |
Public on Apr 12, 2021 |
| Title |
RNA-Seq of LNCaP human prostate cancer cells with knockdown of MAP3K7 and/or CHD1 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify transcriptome changes resulting from loss of each of these genes, as well as their effects on androgen signaling.
Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
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| Overall design |
mRNA profiles of LNCaP human prostate cancer cells engineered with shControl, shMAP3K7, shCHD1, and both (shMAP3K7 and shCHD1), with and without 1nM R1881 were generated by RNAsequencing and compared to identify differentially expressed genes between the groups.
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| Contributor(s) |
Jillson LK, Costello JC, Cramer SD |
| Citation(s) |
33846123 |
| |
| Submission date |
Mar 10, 2021 |
| Last update date |
Jul 13, 2021 |
| Contact name |
Lauren Jillson |
| E-mail(s) |
lauren.jillson@ucdenver.edu
|
| Organization name |
University of Colorado Anschutz Medical Campus
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| Department |
Pharmacology
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| Lab |
Scott Cramer
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| Street address |
12801 E 17th Avenue, Room L18-6213, Mail stop 8303
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| City |
Aurora |
| State/province |
Colorado |
| ZIP/Postal code |
80045 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE168671 |
MAP3K7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of CHD1 |
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| Relations |
| BioProject |
PRJNA713349 |
| SRA |
SRP310158 |
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