Abstract Genistein, a soy isoflavone, has been shown to have anticancer effects on various cancers in vitro and in vivo including renal cancer. Long non-coding RNAs (lncRNAs) are differentially expressed in various tissues and have important functions in cellular processes such as cell proliferation, motility and apoptosis in various malignancies. HOX transcript antisense RNA (HOTAIR) is a lncRNA localized in the Homeobox C gene cluster on chromosome 12. HOTAIR interacts with the polycomb repressive complex 2 (PRC2), which enhances H3K27 trimethylation and represses the expression of tumor suppressors. In various cancers, HOTAIR is highly expressed and involved in their progression and metastasis. In this study, we investigated the molecular mechanisms of genistein action through a novel pathway that represses HOTAIR. We found that HOTAIR expression is higher in renal cancer cell lines compared to normal controls. Genistein treatment was found to significantly decrease HOTAIR expression in renal cancer cells (786-O and ACHN cells). Genistein treatment also reduced expression of epithelial-to-mesenchyme transition (EMT)-related proteins (ZEB1, Vimentin and Snail), causing reduced cell migration, invasion, and increased apoptosis. We performed RNA immunoprecipitation assays, and found that genistein inhibits HOTAIR binding to PRC2. One of the other EMT markers, a tight junction protein ZO-1, is upregulated by genistein. We are currently investigating if genistein represses PRC2 recruitment to the ZO-1 promoter by inhibiting binding of HOTAIR to PRC2. Our results indicate that genistein is a potent therapeutic agent for renal cancer. Citation Format: Mitsuho Imai-Sumida, Shahana Majid, Pritha Dasgupta, Priyanka Kulkarni, Sharanjot Saini, Divya Bhagirath, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura. Genistein inhibits renal cancer progression through long non-coding RNA HOTAIR suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3449. doi:10.1158/1538-7445.AM2017-3449