Identification of a novel YAP–14-3-3ζ negative feedback loop in gastric cancer

// Bin Zhang 1 , Aihua Gong 1 , Hui Shi 1 , Qingli Bie 1 , Zhaofeng Liang 1 , Peipei Wu 1 , Fei Mao 1 , Hui Qian 1 and Wenrong Xu 1, 2 1 Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China 2 The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, P.R. China Correspondence to: Wenrong Xu email: icls@ujs.edu.cn Hui Qian email: lstmmmlst@163.com Keywords: YAP, 14-3-3ζ, MDM2, hippo, gastric cancer Received: April 04, 2017      Accepted: May 09, 2017      Published: May 19, 2017 ABSTRACT Growing evidence indicates that 14-3-3ζ and yes-associated protein (YAP) substantially promote tumorigenesis and tumor development. However, the regulatory mechanism underlying these two proteins remains unknown. Herein, we report a new regulatory role of 14-3-3ζ in the phosphorylation of YAP and the feedback inhibition of 14-3-3ζ by YAP. YAP and 14-3-3ζ expression exhibited a negative correlation in gastric cancer (GC) tissues. Moreover, patients with higher YAP and lower 14-3-3ζ expression had poor prognoses. Studies have revealed that 14-3-3ζ promotes cytoplasmic retention and suppresses the transcriptional activity of YAP by inducing its phosphorylation. Furthermore, we observed that the overexpression of YAP significantly reduced the expression of 14-3-3ζ by inducing its ubiquitination. YAP, 14-3-3ζ, and mouse double minute 2 homolog (MDM2) were colocalized, and the knockdown of MDM2 by siRNA attenuated the YAP-induced decrease of 14-3-3ζ. The binding of 14-3-3ζ and MDM2 was also restrained when the expression of YAP was interfered. Our results indicated the presence of a 14-3-3ζ–YAP negative regulatory feedback loop, which has a crucial role in cell proliferation and survival and is a potential target for the clinical treatment of GC.