Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer

Authors

  • Jiayi Wang,

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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    • This work was supported by the Natural Science Foundation of China (grant nos.: 81272292, 81071524, and 81201363) and the 5810 training program (assigned to J.Y.W.) from Shanghai Tenth People's Hospital.These authors contributed equally to this study.

  • Lifang Ma,

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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    • This work was supported by the Natural Science Foundation of China (grant nos.: 81272292, 81071524, and 81201363) and the 5810 training program (assigned to J.Y.W.) from Shanghai Tenth People's Hospital.These authors contributed equally to this study.

  • Wenhao Weng,

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Yongxia Qiao,

    1. School of Public Health, Shanghai Jiaotong University school of Medicine, Shanghai, China
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  • Yue Zhang,

    1. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Jiangtu He,

    1. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Hongmei Wang,

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Weifan Xiao,

    1. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Lanlan Li,

    1. Departament of Laboratory Medicine, Chongqing Zhongshan Hospital, Chongqing, China
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  • Qinghua Chu,

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Qiuhui Pan,

    1. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Yongchun Yu,

    1. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Fenyong Sun

    Corresponding author
    • Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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  • Potential conflict of interest: Nothing to report.

Address reprint requests to: Fenyong Sun, M.D., Ph.D., Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, 301 Middle Yanchang Road, Shanghai 200072, China. E-mail: sunfenyong@126.com; fax: +86-21- 66300588; or Yongchun Yu, Ph.D., 301 Middle Yanchang Road, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. E-mail: yueyongchun88@163.com; fax: +86-21-66300588.

Abstract

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)

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