Abstract 3441: A novel lncRNA-mediated YAP1 signaling pathway activation in epithelial ovarian cancer

Abstract

Abstract Background: The long noncoding RNA (lncRNA) urothelial cancer associated 1 (UCA1) is upregulated in many cancer types, including ovarian cancer. In high grade serous ovarian cancers (HGSOCs), we had previously found that UCA1 expression negatively correlates with patients’ total survival and disease-free survival and that UCA1 knockout significantly impairs tumor growth in vivo. In addition, UCA1 promotes ovarian cancer cell growth via activating the YAP1 signaling pathway. Purpose: Our present study aims to dissect the molecular mechanisms underlying YAP1 signaling activation by UCA1. Methods: To characterize the UCA1 interactome, we utilized a modified in vivo RNA antisense purification method (UCA1-iRAP). This UCA1-iRAP method uses streptavidin-coupled magnetic beads to pull down biotin-labeled antisense probes which are complementary to the target RNA. In such a way, UCA1 RNA will be specifically enriched together with its in vivo-associated proteins, RNAs and/or genomic DNA, which can be profiled using mass spectrometry (MS) and next generation sequencing (NGS), respectively. Results: Using UCA1-iRAP RNA-Seq and UCA1-iRAP protein MS, we comprehensively annotated the UCA1-interacting RNAs as well as UCA1-associated proteins. Interestingly many of the proteins identified were not known to have RNA-binding potential. Integration of NGS and MS data with multilayered functional and molecular characterization of UCA1 knockout, knockdown and overexpression models identified a YAP1 modulator involved in UCA1-mediated regulation of YAP1 signaling. Through repressing this YAP1 modulator via direct RNA-protein interaction, UCA1 promotes nuclear translocation of YAP1, resulting in activation of YAP1 target genes expression. Conclusions: Our analyses indicate, for the first time, that UCA1 promotes ovarian cancer cell growth by activating YAP1 signaling via direct interaction with a YAP1 modulator. The interaction between UCA1 and this YAP1 modulator leads to activation of YAP1 signaling by nuclear translocation of YAP1. In summary, we characterize a novel UCA1-YAP1 signaling axis active in HGSOCs and also reveal that oncogenic lncRNA’s binding potential of cytoplasmic signaling proteins could be a common mechanism of post-translational control of signaling pathways deregulated in cancer. Note: This abstract was not presented at the meeting. Citation Format: Xianzhi Lin, Rosario I. Corona, Simon A. Gayther, Dennis L. Hazelett, Kate Lawrenson. A novel lncRNA-mediated YAP1 signaling pathway activation in epithelial ovarian cancer [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 3441. doi:10.1158/1538-7445.AM2017-3441