CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

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 and Martin K. Thomsen ()
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Huiqiang Cai: Aarhus University
Bin Zhang: King Abdullah University of Science and Technology (KAUST)
Johanne Ahrenfeldt: Aarhus University
Justin V. Joseph: Aarhus University
Maria Riedel: Aarhus University
Zongliang Gao: Aarhus University
Sofie K. Thomsen: Aarhus University
Ditte S. Christensen: Aarhus University
Rasmus O. Bak: Aarhus University
Henrik Hager: Aarhus University Hospital
Mikkel H. Vendelbo: Aarhus University Hospital
Xin Gao: King Abdullah University of Science and Technology (KAUST)
Nicolai Birkbak: Aarhus University
Martin K. Thomsen: Aarhus University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46370-0

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