Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis and yet their mechanistic role remains challenging to characterize. Here, we present LncRNA Interpreter, a strategy integrating functional proteomics with interacting proteins to characterize lncRNAs. Its robustness is exemplified by lncRNA Urothelial Cancer Associated 1 (UCA1), a driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 inhibits Hippo signaling pathway and in vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as direct binding partner. Loss-of-function experiments show that AMOT mediates Hippo signaling pathway inhibition by UCA1. UCA1 enhances the AMOT-YAP interaction to prevent YAP phosphorylation and facilitate its nuclear translocation. Together, our LncRNA Interpreter pipeline identified UCA1 as an lncRNA regulator of the Hippo signaling pathway and highlighted the UCA1-AMOT-YAP signaling axis in ovarian cancer development. LncRNA Interpreter can readily be applied to other lncRNAs implicated in complex diseases. Citation Format: Xianzhi Lin, Tassja J. Spindler, Marcos A de Souza Fonseca, Rosario I. Corona, Ji-Heui Seo, Felipe S Dezem, Lewyn Li, Janet M. Lee, Henry W. Long, Thomas A. Sellers, Beth Y. Karlan, Houtan Noushmehr, Matthew L. Freedman, Simon A. Gayther, Kate Lawrenson. Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A30.