Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation

• DOI: 10.1073/pnas.1800621115
• Publication Date: 2018-07-02T19:09:52Z
• Authors: Jiuli Zhou; Yongji Zeng; Lian Cui; Xingcheng Chen; Seth Stauffer; Zhan Wang; Fang Yu; Subodh M. Lele; Geoffrey A. Talmon; Adrian R. Black; Yuanhong Chen; Jixin Dong
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Mice, Nude; Mitosis; Cell Cycle Proteins; YAP-Signaling Proteins; Cyclin-Dependent Kinase 8; Phosphoproteins; Zyxin; Neoplasm Proteins; 3. Good health; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Colonic Neoplasms; Animals; Humans; Female; Phosphorylation; Adaptor Proteins, Signal Transducing; Transcription Factors

Significance Zyxin is a member of the cell–cell adhesion complex and controls cell cytoskeleton and motility. Analysis from clinical samples revealed that Zyxin is highly expressed in colon cancer compared with normal tissue, suggesting an oncogenic role for Zyxin in cancer. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, cellular transformation, and tumor formation in xenograft animal models. We also showed that Zyxin is phosphorylated by CDK1 during mitosis. Mitotic phosphorylation is required for Zyxin activity in promoting colon cancer growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. We further showed that CDK8 directly phosphorylates YAP and promotes its activation. These observations identify the Zyxin–CDK8–YAP axis as a potential therapeutic target in cancer.