11 Scopus citations

Abstract

SNAI1 is widely regarded as a master driver of epithelial-mesenchymal transition (EMT) and associated with breast cancer progression and metastasis. This pro-malignant role is strongly linked to posttranslational modification, especially phosphorylation, which controls its protein levels and subcellular localization. While multiple kinases are implicated in regulation of SNAI1 stability, the precise mechanism by which SNAI1 is stabilized in tumors remains to be fully elucidated. Methods: A series of in vitro and in vivo experiments were conducted to reveal the regulation of SNAI1 by Serine/Threonine Kinase 39 (STK39) and the role of STK39 in breast cancer metastasis. Results: We identified STK39, a member of Stem 20-like serine/threonine kinase family, as a novel posttranslational regulator that enhances the stability of SNAI1. Inhibition of STK39 via knockdown or use of a specific inhibitor resulted in SNAI1 destabilization. Mechanistically, STK39 interacted with and phosphorylated SNAI1 at T203, which is critical for its nuclear retention. Functionally, STK39 inhibition markedly impaired the EMT phenotype and decreased tumor cell migration, invasion, and metastasis both in vitro and in vivo. These effects were rescued by ectopic SNAI1 expression. In addition, depletion of STK39 dramatically enhanced sensitivity to chemotherapeutic agents. Conclusions: Our study demonstrated that STK39 is a key mediator of SNAI1 stability and is associated with the pro-metastatic cellular process, highlighting the STK39-SNAI1 signaling axis as promising therapeutic targets for treatments of metastatic breast cancer.

Original languageEnglish
Pages (from-to)7658-7670
Number of pages13
JournalTheranostics
Volume11
Issue number16
DOIs
StatePublished - 2021

Bibliographical note

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Funding

We thank Dr. Cathy Anthony for critical reading and editing of this manuscript. We thank Heather N. Russell-Simmons for editing the figures. We also thank Drs. Jim McCormick (OHSU) and James Wohlschlegel (UCLA) for providing STK39 WT and KR plasmids. This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). This work was also supported by grants from American Cancer Society Research Scholar Award (RSG13187) and NIH (P20GM121327 and CA230758) to Y Wu.

FundersFunder number
James Wohlschlegel
National Institutes of Health (NIH)CA230758
American Cancer Society-Michigan Cancer Research FundRSG13187
National Institute of General Medical SciencesP20GM121327
University of California, Los Angeles
University of Kentucky Markey Cancer CenterP30CA177558

    Keywords

    • EMT
    • Phosphorylation
    • SNAI1
    • STK39
    • Stabilization

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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