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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo–YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumor-igenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.

Original languageEnglish (US)
Pages (from-to)E6760-E6769
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number29
DOIs
StatePublished - Jul 17 2018

Fingerprint

Zyxin
Colonic Neoplasms
Carcinogenesis
Phosphorylation
Cell Movement
Focal Adhesions
Growth
Actin Cytoskeleton
Oncogenes
Mitosis
Heterografts
Polymerization

Keywords

  • CDK8
  • Colon cancer
  • Hippo–YAP pathway
  • Mitosis
  • Zyxin

ASJC Scopus subject areas

  • General

Cite this

Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation. / Zhou, Jiuli; Zeng, Yongji; Cui, Lian; Chen, Xingcheng; Stauffer, Seth; Wang, Zhan; Yu, Fang; Lele, Subodh M; Talmon, Geoffrey A; Black, Adrian R; Chen, Yuanhong; Dong, Jixin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 29, 17.07.2018, p. E6760-E6769.

Research output: Contribution to journalArticle

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abstract = "Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo–YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumor-igenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.",
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AU - Zeng, Yongji

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AU - Stauffer, Seth

AU - Wang, Zhan

AU - Yu, Fang

AU - Lele, Subodh M

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AU - Black, Adrian R

AU - Chen, Yuanhong

AU - Dong, Jixin

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