Theranostics 2021; 11(16):7658-7670. doi:10.7150/thno.62406

Research Paper

STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation

Zhaoping Qiu1,3, Bo Dong1,3, Weijie Guo3, Rychahou Piotr2,3, Greg Longmore4, Xiuwei Yang1, Zhiyong Yu5, Jiong Deng6, B. Mark Evers2,3, Yadi Wu1,3✉

1. Department of Pharmacology & Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40506, United States.
2. Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY 40506, United States.
3. Markey Cancer Center, the University of Kentucky, College of Medicine, Lexington, KY 40506, United States.
4. Department of Medicine (Oncology), Cell Biology and Physiology, Washington University, St. Louis.
5. Department of Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
6. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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Citation:
Qiu Z, Dong B, Guo W, Piotr R, Longmore G, Yang X, Yu Z, Deng J, Evers BM, Wu Y. STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation. Theranostics 2021; 11(16):7658-7670. doi:10.7150/thno.62406. Available from https://www.thno.org/v11p7658.htm

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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.

Keywords: STK39, SNAI1, EMT, phosphorylation, stabilization