PER2 integrates circadian disruption and pituitary tumorigenesis.

Abstract

Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2, Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2, Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2, Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management.