Cheng, Kit‐Yan

The importance of normal circadian rhythms is underscored by the known relationship between circadian disruption and increased cancer risk. The goal of the present study was to investigate the role of the circadian clock in the regulation of genes encoding products that function in cellular transformation. Microarray analysis was used to evaluate changes in gene expression following siRNA‐mediated knockdown of the circadian clock protein Per 1 in a murine renal collecting duct cell line (mpkCCD c14 ). Several hundred genes underwent significant changes in expression following Per1 knockdown, including 21 genes involved in cellular transformation. Cdkn1a and Cyclin E1, both cell cycle regulators, claudin 1 and 12, involved in tight junction formation, and sFRP1, a regulator of Wnt signaling and a tumor suppressor in renal cell carcinoma, were all confirmed as novel Per1 target genes. In an independent sample set, Cdkn1a, Cyclin E1, Claudin 1 and 12, and sFRP1 were all up‐regulated following Per1 knockdown in mpkCCD c14 cells. The chromophobe subtype of renal cell carcinoma is thought to arise from the collecting duct. Interestingly, dysregulation of the circadian clock genes Per2 and Cry2 was observed in patient chromophobe tumor samples compared to normal tissues. These observations support a role for the circadian clock in the control of cellular transformation in the kidney.