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However, direct in vivo evidence for SKP2 on cancer initiation and prostatic microenvironment is still lacking and a SKP2 humanized mouse model is critical for developing prostate cancer immunoprevention approaches through targeting SKP2. We therefore have established a prostate-specific human\n                    <jats:italic>SKP2<\/jats:italic>\n                    knock-in mouse model driven by an endogenous mouse\n                    <jats:italic>probasin<\/jats:italic>\n                    promoter. Overexpression of hSKP2 induces PIN and low-grade carcinoma. RNA-sequencing analysis revealed significant gene expression alterations in EMT, extracellular matrix, and interferon signaling. Single-cell deconvolution showed an increase of fibroblast population and a decrease of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell and B cell populations. Consistent with these results from the SKP2 humanized mouse, SKP2 protein is overexpressed in human prostatic hyperplasia, PIN and prostate adenocarcinoma compared to normal prostate tissues. Overexpression of\n                    <jats:italic>SKP2<\/jats:italic>\n                    markedly increased cell migration and invasion and induced the gene expression of EMT and interferon pathways. Inhibition of SKP2 signaling by Flavokawain A and C1 reverses EMT and affects EMT and interferon-related gene expression. In addition, paired prostate organoids were derived from SKP2 humanized and wild-type mice for drug screening and validated by known SKP2 inhibitors, Flavokawain A and C1. Both of which selectively decreased viability and altered the morphologies of organoids of h\n                    <jats:italic>SKP2<\/jats:italic>\n                    knock-in rather than wild-type mice. Our studies provide a well-characterized prostate-specific h\n                    <jats:italic>SKP2<\/jats:italic>\n                    knock-in mouse model and offer new mechanistic insights for understanding the oncogenic role of SKP2 in shaping the prostatic microenvironment during early carcinogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-03905-7","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:43:50Z","timestamp":1785545030000},"page":"3984-3996","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The establishment of prostate-specific, SKP2 humanized mice by CRISPR knock-in method reveals neoplastic initiation and microenvironmental reprogramming"],"prefix":"10.1038","volume":"45","author":[{"given":"Liankun","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7151-0575","authenticated-orcid":false,"given":"Yurong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyvyan","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Altaf","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3608-1714","authenticated-orcid":false,"given":"Robert H.","family":"Shoemaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2950-3221","authenticated-orcid":false,"given":"Bang H.","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Uchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Zi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"3905_CR1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/12013","volume":"1","author":"AC Carrano","year":"1999","unstructured":"Carrano AC, Eytan E, Hershko A, Pagano M. 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This study was approved by the Ethics Committee of University of California, Irvine and Frederick National Laboratory for Cancer Research. All patients\u2019 data are deidentified and from public resources and no written informed consent was needed. Animal study was approved by the Institutional Animal Care and Use Committee of University of California, Irvine (protocol #: AUP-19-109).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}