TY - JOUR
T1 - Serine threonine kinase 17A maintains the epithelial state in colorectal cancer cells
AU - Short, Sarah P.
AU - Thompson, Joshua J.
AU - Bilotta, Anthony J.
AU - Chen, Xi
AU - Revetta, Frank L.
AU - Washington, M. Kay
AU - Williams, Christopher S.
N1 - Funding Information:
The authors thank all members of the Williams laboratory for thoughtful discussions about this research project. Additionally, we would like to thank the Vanderbilt Translational Pathology Shared Resource core for assistance with slide preparation and H&E staining, as well as the Vanderbilt Cooperative Human Tissue Network for tissue procurement. This work was supported by NIH R01DK080221 to C.S. Williams, F32DK108492 to S.P. Short, F30DK111107 to J.J. Thompson, and P30DK058404 to M.K. Washington, and the Office of Medical Research, Department of Veterans Affairs I01BX001426 to C.S. Williams. This project was also supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the NIH.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-18-0990
DO - 10.1158/1541-7786.MCR-18-0990
M3 - Article
C2 - 30655319
AN - SCOPUS:85064060407
VL - 17
SP - 882
EP - 894
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 4
ER -