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.

Clinical analysis of the efficacy of radiation therapy for primary high-grade gliomas guided by biological rhythms

“…This study found that the proportion of lymphocytes in the afternoon radiotherapy group was significantly higher than that in the morning radiotherapy group, corresponding to higher overall survival and progression-free survival rates in the afternoon radiotherapy group. This seemingly results from the upregulation of Per2 expression during the afternoon period [45] , as studies suggest that Per2 gene knockout corresponds with notable splenic lymphocyte reductions [46] . The onset of glioma is intrinsically linked to circadian clock gene aberrations.…”

PER2 regulates odontoblastic differentiation of dental papilla cells in vitro via intracellular ATP content and reactive oxygen species levels

“…Per2 is the most frequently studied member of the Per family. As a crucial and powerful clock gene, Per2 has been found to be involved in physio/pathological pathways in tissue development ( McQueen et al, 2018 ), cell differentiation ( Huang et al, 2021 ), cell metabolism ( Grimaldi et al, 2010 ), cell aging ( Levine et al, 2020 ), tumor development ( Guo et al, 2023 ), oxidative stress ( Magnone et al, 2014 ), and neurobiological activities ( Sayson et al, 2023 ). For tooth development, PER2 has recently been identified as a potential regulator ( Huang et al, 2021 ; Jiang et al, 2022 ; Zheng et al, 2011 ).…”

Circadian rhythm disruption and endocrine-related tumors

“…Four to five percent of pituitary adenomas are associated with clinical syndromes like multiple endocrine neoplasia 1 (Carney complex) and familial isolated pituitary adenoma, whose diverse genetic profiles are still under investigation[ 175 ]. A recent work has revealed the role of PER2 , a key clock gene, in the pathogenesis of pituitary adenomas[ 176 ]. In human tissues obtained from prolactinomas and growth hormone-producing adenomas, the expression of several CGs was dysregulated compared to controls, with PER2 being consistently overexpressed.…”

“…Jet-lagged mice that had been inoculated with GH3 cells exhibited a faster rate of tumor growth that had a time-specific pattern[ 176 ]. The timing of higher cell proliferation was different compared to mice with intact circadian rhythm and correlated with elevated Per2 expression.…”

“…The timing of higher cell proliferation was different compared to mice with intact circadian rhythm and correlated with elevated Per2 expression. In other groups of mice, one with estrogen-induced prolactinomas and one with xenograft GH3 tumors, KO of Per2 led to slower progression of the tumors as indicated by decreased Ki67 or smaller tumor mass and volume[ 176 ]. Apparently, Per2 plays an important role in cell cycle regulation, as its loss halts cells in the G2/M phase and negatively affects the number of pituitary cells in mitosis and positively those in apoptosis.…”