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GEO help: Mouse over screen elements for information. |
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Status |
Public on Jul 26, 2017 |
Title |
CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair |
Organisms |
Homo sapiens; Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
BACKGROUND: Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. DESIGN: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss. RESULTS: We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vivo, ex vivo and in a patient with metastatic PCa. Mechanistically, CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair. CONCLUSIONS: Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ and suggest that CHD1 loss may contribute to genomic instability seen in this subset of PCa patients.
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Overall design |
In total, 11 murine samples and 9 human samples were analyzed. For each genotype, there are 3 to 6 replicates.
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Contributor(s) |
Shenoy T, Boysen G, Wang M, Xu Q, Guo W, Koh F, Wang C, Zhang L, Wang Y, Gil V, Aziz S, Nava Rodrigues D, Christova R, Rodrigues D, Crespo M, Resign P, Tunariu N, Riisnaes R, Zafeiriohu Z, Flohr P, Yuan W, Knight E, Swain A, Ramalho-Santos M, Xu D, de Bono J, Wu H |
Citation(s) |
28383660 |
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Submission date |
Jul 20, 2016 |
Last update date |
May 15, 2019 |
Contact name |
Weilong Guo |
E-mail(s) |
guoweilong@126.com
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Organization name |
Peking University
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Street address |
Intergrated Science Building
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City |
Beijing |
ZIP/Postal code |
100871 |
Country |
China |
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Platforms (2) |
GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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Samples (20)
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Relations |
BioProject |
PRJNA330629 |
SRA |
SRP078982 |
Supplementary file |
Size |
Download |
File type/resource |
GSE84610_human_RNAseq_summary.txt.gz |
741.7 Kb |
(ftp)(http) |
TXT |
GSE84610_mouse_RNAseq_summary.txt.gz |
921.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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