Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway.

Niu Zhanfeng,Wang Chengquan,Yin Lei,Liu Wenbin,Xia Hechun,Ma Dede,Wang Jun,Zhang Lijian

doi:10.18632/oncotarget.8439

Niu Zhanfeng, Wang Chengquan + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.8439

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Abstract

The Period2 (Per2) gene is an essential component of the mammalian circadian clock and is strongly linked to glioma occurrence and its response to radiotherapy. Here, we examined the role of Per2 in the response to X-ray-induced DNA damage in U343 glioma cells and in a mouse cancer model. Following low dose X-ray irradiation, we observed that lowering Per2 expression using RNAi reduces DNA damage and cell death in U343 cells and glioma tissue. Additionally, Per2 was associated with increased TP53 activity and was involved in the DNA damage during TP53-mediated apoptosis. These findings suggest that Per2, a core circadian gene, is not only a tumor suppressor gene but can also be regarded as an upstream regulator of TP53. It thus appears that Per2 is an important inhibitor of tumor growth that acts by increasing TP53 expression, DNA damage repair, and apoptosis.

Highlights

Gliomas are amongst the most lethal forms of cancer [1, 2]
We determined Per2 mRNA and protein expression levels in the U343MG cell line, which overexpresses murine double minute 2 (MDM2) and maintains wild-type p53 levels, using quantitative real-time PCR and Western blotting, respectively. Both Per2 mRNA and protein levels were notably reduced in the U343 cells transfected with shRNA-PER2 relative to the shRNA-transfected control U343 cells (P < 0.05; n = 3) or blank-treated U343 cells(the blank treatment is the normal U343 cells) (P < 0.05; n = 3; Figure 1)
Circadian Per2 disruption has been implicated in cell cycle dysfunction and apoptosis, which was evident by the aberrant rhythmic expression of the cell cycle gene cyclin D1 as well as the negative p53 regulator MDM2 [27]

Summary

Introduction

Gliomas are amongst the most lethal forms of cancer [1, 2]. Their invasive growth makes complete tumor resection very difficult leading to high lethality [3]. Overexpression and/or mutations in the Per gene correlate with enhanced tumor growth in breast cancer, colon cancer, and lymphoma, along with altered expression of TP53 and the oncogenes BCLxl, BCL-2, cyclinB1, cyclin D, cyclin E, and c-myc [11,12,13,14,15,16]. Per has been linked to DNA damage response pathways [17], and low Per expression may increase the efficacy of radiotherapy against glioma by promoting apoptosis [18,19,20]

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