Carcinogenesis
Carcinogenesis
5 years ago

Transcriptional and Posttranscriptional Upregulation of p27 Mediates Growth Inhibition of Isorhapontigenin (ISO) on Human Bladder Cancer Cells.

Chuanshu Huang, Guosong Jiang, Haishan Huang, Honglei Jin, Jingxia Li, Fei Xie, Jingjing Wang, Chao Huang, Junlan Zhu, Yawei Li
There are few approved drugs available for the treatment of muscle invasive bladder cancer. Recently, we 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. Herein, we found that treatment of bladder cancer (BC) cells with Isorhapontigenin resulted in a significant upregulation of p27, which was also observed in ISO-treated mouse BCs that were induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Importantly, knockdown of p27 caused a decline in the Isorhapontigenin-induced G0-G1 growth arrest and reversed ISO suppression of anchorage-independent growth in BC 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 BC 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 BC cell growth. Our results not only provide novel insight into understanding of the underlying mechanism related to regulation of muscle invasive BC cell growth, but also identify new roles and mechanisms underlying ISO inhibition of BC cell growth.

Publisher URL: http://doi.org/10.1093/carcin/bgy015

DOI: 10.1093/carcin/bgy015

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