LAUSR

Simvastatin (SMV), a lipophilic statin used for lowering cholesterol, inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the key enzyme of the mevalonate pathway. Studies have shown that cancer cells express deregulated level of HMGCR and statins exert antitumoral activities. We first assessed correlation between mevalonate pathway genes and DP103 (DDX20, Gemin-3) in 1,325 breast cancer patients and observed a positive correlation between DP103 and the mevalonate pathway genes. Having this data, we then proceeded to explore the effect of statins on DP103 expression. We used various in vitro cell lines and in vivo statin clinical trial patients’ specimens, mouse xenograft, mouse intravenous tail injection, and Drosophila (wild-type vs. Gemin-3 knockdown vs. Gemin-3 overexpression flies) models. We show exposure to statin decreases the expression of DP103. Through a series of add-back experiments, we show that the decrease in DP103 expression by statins is via the mevalonate pathway and downstream of RhoA. In clinical specimens, we observed breast cancer patients with high baseline DP103 positively correlate with high baseline YAP-TEAD expression. Having known that SUMOylation of YAP maintains its activity and that DP103 is a critical enhancer of the SUMOlyation machinery, we showed through a series of experiments that a physical interaction between DP103 and YAP is crucial for maintaining SUMOylation of YAP, thereby decreasing its ubiquitination and degradation. Interestingly, we also identified for the first time that DP103 is a direct target of YAP-TEAD complex and that maintenance of DP103 expression is needed as a positive feedback, forming an Achilles heel for sustained YAP-TEAD activity. Citation Format: Xianning Lai, Tingting Wang, Tuan Zea Tan, Patrick J Casey, Wanjin Hong, Marius Sudol, Vinay Tergaonkar, Soo Chin Lee, Alan Prem Kumar. DEAD-box RNA helicase DP103 enhances YAP sumoylation for YAP-TEAD dependence and statin sensitivity in triple-negative breast 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 A28.