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.
Highlights
The incidence of gastric cancer (GC) has decreased over the past few decades; it remains the fourth most common cancer and second leading cause of death from cancer worldwide [1,2,3]
These results indicate a contrasting expression pattern of yes-associated protein (YAP) and 14-3-3ζ and reveal a linear correlation in GC tissues that may affect the prognoses of patients with GC
The Hippo pathway plays a crucial role in organ size control and tissue homeostasis [37]
Summary
The incidence of gastric cancer (GC) has decreased over the past few decades; it remains the fourth most common cancer and second leading cause of death from cancer worldwide [1,2,3]. Considerable effort has been devoted to elucidating its underlying mechanisms and discovering novel diagnostic biomarkers and therapeutic targets. Extensive knowledge has been obtained regarding biomarkers and the therapeutic targets that affect cancer cell properties, few studies have investigated the role of mutual regulation among these proteins in GC or their underlying mechanisms. YAP is strongly expressed in gastric adenocarcinomas, and the knockdown of YAP may inhibit GC cell proliferation [17]. These findings reveal that the inhibitory molecules of YAP may be effective therapeutic targets in GC
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