Identifying CSNK1E as a therapeutic target in thyroid cancer among the core circadian clock genes.

Abstract

Previous studies have shown that thyroid malignancies can alter the transcriptional oscillations of circadian clock genes. In this study, we screened the expression of core circadian clock genes in thyroid neoplasms and found that CSNK1E, NPAS2, and TIMELESS were upregulated, while ARNTL, CRY1, CRY2, PER2, and RORA were downregulated during the progression and dedifferentiation of thyroid cancer. Immunohistochemical analysis further confirmed an increase in CSNK1E expression parallel to the loss of tumor differentiation. To investigate the potential therapeutic implications, we treated thyroid cancer cell lines with two different CSNK1E inhibitors: PF670462 and IC261. Both inhibitors resulted in growth inhibition in monolayer and three-dimensional spheroid cultures. This growth inhibition was accompanied by G2/M cell cycle arrest and a decrease in CDK4 and cyclin D1 expression. Moreover, CSNK1E inhibitors suppressed cell migration and invasion and reduced the expression of epithelial-mesenchymal transition markers. In vivo experiments using xenograft models showed that the administration of IC261 significantly restrained tumor growth and decreased the Ki-67 index of the xenograft tumors. In conclusion, our study provides evidence of aberrant CSNK1E expression in thyroid cancer dedifferentiation and highlights the potential therapeutic value of targeting CSNK1E.