Abstract LB-55: UTX epigenetically regulates epithelial-mesenchymal transition-associated breast cancer stem cell properties independently of EZH2

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA UTX is a histone H3 lysine 27 (H3K27) demethylase that can antagonize a histone methyltransferase EZH2. Although H3K27 trimethylation by EZH2 has been involved in cancer-related biological processes including tumorigenesis, invasion, and stemness, the role of UTX in cancer progression has not been identified yet. In this study, we demonstrated an EZH2-independent tumor suppressive function of UTX in breast cancer. We found that loss of UTX enhanced self-renewal and tumorigenicity of breast cancer stem cells (CSCs) and also promoted CSC-associated epithelial-mesenchymal transition (EMT) through upregulating EMT-transcription factors (EMT-TFs), Snail, ZEB1 and ZEB2. Moreover, UTX positively regulated E-cadherin, a key marker of EMT, via these EMT-TFs. Notably, we identified that UTX facilitated epigenetic silencing of EMT-TFs by cooperating with c-Myc and various epigenetic modulators independently of EZH2. In the promoter regions of EMT-TFs, the levels of histone H3K4 methylation and H3 acetylation were inhibited by UTX. We also found that UTX formed a transcriptional repressive complex with LSD1, HDAC1, and DNMT1 for recruiting them to the promoters of EMT-TFs, while loss of UTX led to recruitment of c-Myc and p300 transcriptional active complex to these promoters. These effects were dependent on c-Myc, as UTX knockdown-induced epigenetic alterations of EMT-TFs and breast cancer stemness were reversed by siRNA-mediated c-Myc repression. Taken together, these data indicated that UTX negatively regulates EMT-induced breast CSCs by epigenetically repressing EMT-TFs independently of H3K27 methylation, suggesting a novel tumor suppressive role of UTX in breast cancer. Citation Format: Hee-Joo Choi, Ji-Hye Park, Mi-Kyung Park, Chang-Hoon Lee, Jeong-Yeon Lee, Gu Kong. UTX epigenetically regulates epithelial-mesenchymal transition-associated breast cancer stem cell properties independently of EZH2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-55. doi:10.1158/1538-7445.AM2014-LB-55