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Updated: Jun 22, 2026
Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster
Huiqiang Cai1, Bin Zhang2,3, Johanne Ahrenfeldt4,5
1Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Abstract:
Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.
Insights
Targeting tumor suppressor genes and epigenetic factors in mice revealed key interactions driving metastatic prostate cancer (PCa) progression. Gene expression signatures from this study predict patient survival and distinguish primary from metastatic PCa.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic prostate cancer (PCa) presents a major therapeutic challenge due to high mortality rates.
- Understanding the genetic and epigenetic drivers of PCa metastasis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of specific tumor suppressor genes and epigenetic factors in prostate cancer metastasis using a mouse model.
- To identify genetic interactions that influence metastatic progression and to explore their potential as therapeutic targets.
Main Methods:
- CRISPR-Cas9 gene editing was employed in vivo to target tumor suppressor genes (Pten, Trp53, Rb1, Stk11, RnaseL) and epigenetic factors (Kmt2c, Kmt2d, Zbtb16) in mouse prostate.
- Whole genome sequencing and RNA sequencing were performed to analyze mutational landscapes and gene expression changes.
- Depletion of specific genes in a conserved genomic region (chr5qE1) was assessed for its effect on metastasis.
Main Results:
- Depletion of tumor suppressor genes alone did not result in metastasis within eight weeks.
- Simultaneous depletion of epigenetic factors led to the presence of lung metastases in all mice.
- RNA sequencing revealed significant gene dysregulation, particularly in the chr5qE1 region regulated by KMT2C, where Odam and Cabs1 depletion prevented metastasis.
- Gene expression signatures correlated with progression-free and overall survival and differentiated primary from metastatic human prostate cancer.
Conclusions:
- Classical tumor suppressor genes and epigenetic modulators exhibit positive genetic interactions that promote metastatic prostate cancer progression.
- The identified gene expression signatures can serve as prognostic biomarkers for PCa.
- Targeting specific genes within the chr5qE1 region presents a potential therapeutic strategy for inhibiting PCa metastasis.
