Abstract 2306: Transcriptional and post-transcriptional upregulation of p27 mediates growth inhibition of isorhapontigenin/ISO on human bladder cancer cells

Abstract

Abstract Our recent studies have demonstrated that Isorhapontigenin (ISO), a new derivative isolated from the Chinese herb Gnetum Cleistostachyum, effectively induces cell-cycle arrest at the G0/G1 phase and inhibits anchorage-independent cell growth through the miR-137/Sp1/cyclin D1 axis in human muscle invasive bladder cancer cells both in vitro and in vivo. Herein, we found that treatment of muscle invasive bladder cancer cells with ISO resulted in a significant upregulation of p27, a key cyclin-dependent kinase inhibitor. Importantly, knockdown of p27 caused a decline in the ISO-induced G0-G1 growth arrest and reversed ISO suppression of anchorage-independent growth in bladder cancer cells. Mechanistic studies revealed that ISO promoted p27 expression at mRNA transcription level through increasing direct binding of FOXO1 to its promoter, while knockdown of FOXO1 attenuated ISO inhibition of cell growth. On the other hand, ISO upregulated the 3'UTR activity of p27, which was accompanied by a reduction of miR-182 expression. In line with these observations, ectopic expression of miR-182 significantly blocked p27 3'UTR activity, whereas mutation of the miR-182 binding site at p27 mRNA 3'UTR effectively reversed this inhibition. Accordingly, ectopic expression of miR-182 also attenuated ISO upregulation of p27 expression and impaired ISO inhibition of cancer cell growth. Our results not only provide novel insight into understanding of the underlying mechanism related to regulation of muscle invasive bladder cancer cell growth, but also identify new roles and mechanisms underlying ISO inhibition of the growth of human bladder cancer cells. Citation Format: Jiheng Xu, Jingxia Li, Chuanshu Huang, Haishan Huang, Guosong Jiang. Transcriptional and post-transcriptional upregulation of p27 mediates growth inhibition of isorhapontigenin/ISO on human bladder cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2306.