Serine threonine kinase 17A maintains the epithelial state in colorectal cancer cells

Sarah P. Short, Joshua J. Thompson, Anthony J. Bilotta, Xi Chen, Frank L. Revetta, M. Kay Washington, Christopher S. Williams

Research output: Contribution to journalArticle

Abstract

Serine threonine kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer has not been established. Here, we have analyzed STK17A in colorectal cancer and demonstrated decreased expression of STK17A in primary tumors, which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of colorectal cancer cell lines to treatment with the chemotherapeutic 5-fluorouracil. Instead, STK17A knockdown induced a robust mesenchymal phenotype consistent with the epithelial-mesenchymal transition, including spindlelike cell morphology, decreased expression of adherens junction proteins, and increased migration and invasion. Additionally, overexpression of STK17A decreased cell size and induced widespread membrane blebbing, a phenotype often associated with activation of cell contractility. Indeed, STK17Aoverexpressing cells displayed heightened phosphorylation of myosin light chain in a manner dependent on STK17A catalytic activity. Finally, patient-derived tumor organoid cultures were used to more accurately determine STK17A's effect in primary human tumor cells. Loss of STK17A induced morphologic changes, decreased E-cadherin, increased invasion, and augmented organoid attachment on 2D substrates, all together suggesting a more metastatic phenotype. Collectively, these data indicate a novel role for STK17A in the regulation of epithelial phenotypes and indicate its functional contribution to colorectal cancer invasion and metastasis. Implications: Loss of serine threonine kinase 17A occurs in colorectal cancer metastasis, induces mesenchymal morphologies, and contributes to tumor cell invasion and migration in colorectal cancer.

Original languageEnglish (US)
Pages (from-to)882-894
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number4
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Short, S. P., Thompson, J. J., Bilotta, A. J., Chen, X., Revetta, F. L., Washington, M. K., & Williams, C. S. (2019). Serine threonine kinase 17A maintains the epithelial state in colorectal cancer cells. Molecular Cancer Research, 17(4), 882-894. https://doi.org/10.1158/1541-7786.MCR-18-0990