Abstract 3458: Role of zyxin in mitosis and colon cancer

Abstract

Abstract Zyxin is a LIM domain protein that is concentrated at sites of cell-cell adhesion, where it is proposed to dock proteins involved in cytoskeletal dynamics and signaling. Recently, Zyxin has been shown to promote LATS degradation and YAP activation in Hippo Pathway. Here, We have identified a novel mechanism for phospho-regulation of Zyxin in mitosis and its biological significance in colon cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates Zyxin in vitro and in vivo at serine 281, serine 308 and serine 344 during antimitotic drug-induced G2/M phase arrest and unperturbed mitosis. Moreover, Zyxin mitotic phosphorylation-deficient mutant (Zyxin3A, harboring S281A/S308A/S344A) was sufficient to suppress colon cancer cell proliferation and migration. We further demonstrated that depletion of Zyxin resulted in impaired colon cancer tumorigenesis in vitro and in vivo through inhibiting F-actin cytoskeleton and YAP activity. Importantly, these observations could be fully rescued by re-expression of wild type Zyxin, but not Zyxin-3A mutant. Expression profile analysis revealed CDK8 (cyclin-dependent kinase 8) as a mediator downstream Zyxin/YAP. Inhibition of CDK8 phenocopied knockdown of Zyxin in colon cancer cells. Ectopic expression of CDK8 substantially restored the tumorigenic ability of Zyxin depletion cells in vitro and in vivo. Expression levels of Zyxin and CDK8 are both elevated in colon tumors and are negatively correlated with survival. Together, our findings reveal a novel layer of regulation for Zyxin in mitosis and define the Zyxin-YAP-CDK8 axis as a novel oncogenic regulator in colon cancer. Citation Format: JIULI ZHOU, Jixin Dong, YUANHONG CHEN, XINGCHENG CHEN, Seth Stauffer, Yongji Zeng. Role of zyxin in mitosis and colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3458. doi:10.1158/1538-7445.AM2017-3458