Abstract 1: Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents

作者：Liankun Song, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, Xiaolin Zi · 发表于：Cancer Research · 年份：2022 · DOI：10.1158/1538-7445.am2022-1 · 研究领域：Ubiquitin and proteasome pathways、14-3-3 protein interactions、Cancer-related Molecular Pathways

Abstract S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten, or p53 deficient mice. We, therefore, aim to establish CRISPR human Skp2 (hSkp2) knock-in in the prostates of mice to study the molecular profiling features in prostate carcinogenesis. Prostate weights increased in transgenic mice and overexpression of hSkp2 induced prostatic lesions including hyperplasia, mouse prostate intraepithelial neoplasia (mPIN), and carcinoma, which suggested the initial role of hSkp2 in early prostate carcinogenesis. RNAseq results revealed Myl3 and Ctgf as the top down-expressed and up-expressed genes respectively in hSkp2 mice prostates. Gene set enrichment analysis (GSEA) demonstrated the significant upregulations of ribosome and proteasome pathways which had similar alterations in the human prostate cancer dataset with Skp2 overexpression, suggesting the potential role of ribosome biogenesis in prostate tumorigenesis and for drug development. In addition, Skp2 organoids derived from transgenic mice prostates were being developed for convenient and efficient screening of specific Skp2 inhibitors. Flavokawain A (FKA) and Skp2 inhibitor C1 both selectively decreased the viability and altered the morphologies of hSkp2 organoids, meanwhile FKA exhibited less toxicity on wild-type organoids. Citation Format: Liankun Song, Vyvyan Nguyen,...