Mutual Interaction Between Yap And Creb Promotes Tumorigenesis in Liver Cancer

• DOI: 10.1002/hep.26420
• Publication Date: 2013-03-26T17:37:17Z
• Authors: Jiayi Wang; Lifang Ma; Wenhao Weng; Yongxia Qiao; Yue Zhang; Jiangtu He; Hongmei Wang; Weifan Xiao; Lanlan Li; Qinghua Chu; Qiuhui Pan; Yongchun Yu; Fenyong Sun
• Keywords: Feedback, Physiological; 0301 basic medicine; Carcinoma, Hepatocellular; Carcinogenesis; Cell Survival; Liver Neoplasms; Mice, Nude; In Vitro Techniques; Phosphoproteins; 3. Good health; Mitogen-Activated Protein Kinase 14; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Animals; Heterografts; Homeostasis; Humans; Phosphorylation; Cyclic AMP Response Element-Binding Protein; Cells, Cultured; Adaptor Proteins, Signal Transducing

Yes-associated protein (YAP), the downstream effecter of the Hippo-signaling pathway as well as cyclic adenosine monophosphate response element-binding protein (CREB), has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interact with each other. In this study, we found that YAP-CREB interaction is critical for liver cancer cell survival and maintenance of transformative phenotypes, both in vitro and in vivo. Moreover, both CREB and YAP proteins are highly expressed in a subset of human liver cancer samples and are closely correlated. Mechanistically, CREB promotes YAP transcriptional output through binding to −608/−439, a novel region from the YAP promoter. By contrast, YAP promotes protein stabilization of CREB through interaction with mitogen-activated protein kinase 14 (MAPK14/p38) and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Gain-of-function and loss-of-function studies demonstrated that phosphorylation of CREB by MAPK14/p38 at ser133 ultimately leads to its degradation. Such effects can be enhanced by BTRC through phosphorylation of MAPK14/p38 at Thr180/Tyr182. However, YAP negatively controls phosphorylation of MAPK14/p38 through inhibition of BTRC expression. Conclusion: There is a novel positive autoregulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting that YAP and CREB form a nexus to integrate the protein kinase A, Hippo/YAP, and MAPK14/p38 pathways in cancer cells and thus may be helpful in the development of effective diagnosis and treatment strategies against liver cancer. (Hepatology 2013;53:1011–1020)