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

Autor: Cai H; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Zhang B; Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia., Ahrenfeldt J; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Joseph JV; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Riedel M; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Gao Z; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Thomsen SK; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Christensen DS; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Bak RO; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Hager H; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark., Vendelbo MH; Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark., Gao X; Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia., Birkbak N; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Thomsen MK; Department of Biomedicine, Aarhus University, Aarhus, Denmark. mkt@biomed.au.dk.; Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark. mkt@biomed.au.dk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 07; Vol. 15 (1), pp. 2088. Date of Electronic Publication: 2024 Mar 07.
DOI: 10.1038/s41467-024-46370-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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