Prostate-specific CRISPR knock-in of human SKP2 induces prostatic intraepithelial neoplasia and adenocarcinoma and reprograms prostate microenvironment.

ABSTRACT: S-phase kinase associated protein 2 (SKP2), an oncogene and promising therapeutic target, required for spontaneous tumor development in the retinoblastoma protein (pRB), PTEN or p53 deficient mice. We therefore have established a prostate specific CRISPR human SKP2 (hSKP2) knock-in mouse model for studying its role in prostate carcinogenesis. Overexpression of hSKP2 which is driven by endogenous mouse probasin promoter induces prostatic lesions including hyperplasia, mouse prostate intraepithelial neoplasia (mPIN), and low-grade carcinoma and increase prostate weights. Transcriptional profiling by RNA-sequencing analysis revealed significant gene expression alterations in epithelial to mesenchymal transition (EMT), extracellular matrix and interferon signaling in the prostate of hSKP2 knock-in mice compared to wild-type mice. Single cell deconvolution showed an increase of fibroblasts population and a decrease of CD8+T cell and B cell populations in the prostates of hSKP2-knock-in mice. Consistently with these results, overexpression of hSKP2 in human prostate cancer PC3 cells markedly increased cell migration and invasion and induced the gene expression of EMT and interferon pathways, including FMOD, THY1, PFPK, USP18, IL15, etc. In addition, prostate organoids were derived from hSKP2 knock-in and wild -type mouse prostates. Known SKP2 inhibitors Flavokawain A (FKA) and C1 both selectively decrease the viability and alter the morphologies of hSKP2 knock-in versus wild-type prostate organoids. Our studies have provided a new well-characterized prostate-specific hSKP2 knock-in mouse model for testing novel SKP2 targeting agents and new mechanistic insights for understanding an oncogenic role of SKP2 on prostate microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE295398 | GEO | 2026/07/24

REPOSITORIES: GEO