PER2 integrates circadian disruption and pituitary

Guo, Lianxia1; Cen, Haobin1; Weng, Jiaxian1; He, Yiting2; Guo, Xiaocao2; He, Di1; Liu, Kaisheng3,4; Duan, Shuyi5; Yang, Jing5; Zhang, Xiaojian5; Qin, Zifei5; Wan, Yong3,4; Chen, Zhiyong6,7; Wu, Baojian1

2023

10.7150/thno.82995

THERANOSTICS   影响因子和分区

1838-7640

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-1 alpha. HIF-1 alpha 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.

Pituitary adenoma Circadian disruption PER2 Cell cycle Apoptosis

SCI

英语

通讯

National Natural Science Foundation of China[82273040] ; Science and Technology Foundation of Shenzhen[JCYJ20200109144410181] ; Science and Technology Projects in Guangzhou[202201010025] ; National Key R&D Program of China["2020YFC2008300","2020YFC2008304"] ; Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology[2022HYTP045]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000997824000001

IVYSPRING INT PUBL

Web of Science

1.Guangzhou Univ Chinese Med, Inst Mol Rhythm & Metab, Guangzhou, Peoples R China
2.Jinan Univ, Sch Med, Dept Publ Hlth & Prevent Med, Guangzhou, Peoples R China
3.Jinan Univ, Shenzhen Peoples Hosp, Guangdong Prov Clin Res Ctr Geriatr, Shenzhen Clin Res Ctr Geriatr,Clin Med Coll 2, Guangzhou, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen, Guangdong, Peoples R China
5.Zhengzhou Univ, Dept Pharm, Affiliated Hosp 1, Zhengzhou 450052, Peoples R China
6.Jinan Univ, Dept Neurosurg, Affiliated Hosp 1, Guangzhou, Peoples R China
7.Jinan Univ, Minimally Invas Treatment Ctr Pituitary Adenoma, Guangzhou, Peoples R China

Guo, Lianxia,Cen, Haobin,Weng, Jiaxian,et al. PER2 integrates circadian disruption and pituitary[J]. THERANOSTICS,2023,13(8).

Guo, Lianxia.,Cen, Haobin.,Weng, Jiaxian.,He, Yiting.,Guo, Xiaocao.,...&Wu, Baojian.(2023).PER2 integrates circadian disruption and pituitary.THERANOSTICS,13(8).

Guo, Lianxia,et al."PER2 integrates circadian disruption and pituitary".THERANOSTICS 13.8(2023).