Title: Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity Both In Vitro and In Vivo.
Authors: Zeng, Xingruo; Xu, Zhou; Gu, Jiayan; Huang, Haishan; Gao, Guangxun; Zhang, Xiaoru; Li, Jingxia; Jin, Honglei; Jiang, Guosong; Sun, Hong; Huang, Chuanshu
Published In Mol Cancer Ther, (2016 Mar)
Abstract: Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell-cycle G0-G1 arrest as well as downregulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In the current study, the potential ISO inhibition of bladder tumor formation has been explored in a xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anticancer activities have been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by directly targeting Sp1 mRNA 3'-untranslated region (UTR). Similar to ISO treatment, ectopic expression of miR-137 alone led to G0-G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by overexpression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced inhibition of Sp1/Cyclin D1 expression, induction of G0-G1 cell growth arrest, and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3'-UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0-G1 growth arrest, and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anticancer activity of ISO in the therapy of human bladder cancer.
PubMed ID: 26832795
MeSH Terms: 3' Untranslated Regions; Animals; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Proliferation/drug effects; Disease Models, Animal; Ectopic Gene Expression; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic/drug effects*; Humans; Mice; MicroRNAs/chemistry; MicroRNAs/genetics*; Protein Biosynthesis/drug effects; RNA Interference*; RNA, Messenger/chemistry; RNA, Messenger/genetics; Sp1 Transcription Factor/genetics*; Sp1 Transcription Factor/metabolism; Stilbenes/pharmacology*; Tumor Burden/drug effects; Tumor Burden/genetics; Urinary Bladder Neoplasms/drug therapy; Urinary Bladder Neoplasms/genetics; Urinary Bladder Neoplasms/metabolism; Urinary Bladder Neoplasms/pathology; Xenograft Model Antitumor Assays