CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
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 withou...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46370-0 |
| _version_ | 1797266721803862016 |
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| author | Huiqiang Cai Bin Zhang Johanne Ahrenfeldt Justin V. Joseph Maria Riedel Zongliang Gao Sofie K. Thomsen Ditte S. Christensen Rasmus O. Bak Henrik Hager Mikkel H. Vendelbo Xin Gao Nicolai Birkbak Martin K. Thomsen |
| author_facet | Huiqiang Cai Bin Zhang Johanne Ahrenfeldt Justin V. Joseph Maria Riedel Zongliang Gao Sofie K. Thomsen Ditte S. Christensen Rasmus O. Bak Henrik Hager Mikkel H. Vendelbo Xin Gao Nicolai Birkbak Martin K. Thomsen |
| author_sort | Huiqiang Cai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-25T01:05:12Z |
| format | Article |
| id | doaj.art-b26426d9b48c4a0dba41510dd87eb43f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-25T01:05:12Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b26426d9b48c4a0dba41510dd87eb43f2024-03-10T12:17:03ZengNature PortfolioNature Communications2041-17232024-03-0115111810.1038/s41467-024-46370-0CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expressionHuiqiang Cai0Bin Zhang1Johanne Ahrenfeldt2Justin V. Joseph3Maria Riedel4Zongliang Gao5Sofie K. Thomsen6Ditte S. Christensen7Rasmus O. Bak8Henrik Hager9Mikkel H. Vendelbo10Xin Gao11Nicolai Birkbak12Martin K. Thomsen13Department of Biomedicine, Aarhus UniversityComputational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST)Department of Clinical Medicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Clinical Medicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Pathology, Aarhus University HospitalDepartment of Nuclear Medicine & PET Centre, Aarhus University HospitalComputational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST)Department of Clinical Medicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityAbstract 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.https://doi.org/10.1038/s41467-024-46370-0 |
| spellingShingle | Huiqiang Cai Bin Zhang Johanne Ahrenfeldt Justin V. Joseph Maria Riedel Zongliang Gao Sofie K. Thomsen Ditte S. Christensen Rasmus O. Bak Henrik Hager Mikkel H. Vendelbo Xin Gao Nicolai Birkbak Martin K. Thomsen CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression Nature Communications |
| title | CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression |
| title_full | CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression |
| title_fullStr | CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression |
| title_full_unstemmed | CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression |
| title_short | CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression |
| title_sort | crispr cas9 model of prostate cancer identifies kmt2c deficiency as a metastatic driver by odam cabs1 gene cluster expression |
| url | https://doi.org/10.1038/s41467-024-46370-0 |
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