Oncotarget

Research Papers:

PP2A inhibitors arrest G2/M transition through JNK/Sp1- dependent down-regulation of CDK1 and autophagy-dependent up-regulation of p21

Fei-Ran Gong _, Meng-Yao Wu, Meng Shen, Qiaoming Zhi, Ze-Kuan Xu, Rong Wang, Wen-Jie Wang, Yang Zong, Zeng-Liang Li, Yadi Wu, Binhua P. Zhou, Kai Chen, Min Tao and Wei Li

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Oncotarget. 2015; 6:18469-18483. https://doi.org/10.18632/oncotarget.4063

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Abstract

Fei-Ran Gong1,2,3,4,5,*, Meng-Yao Wu1,*, Meng Shen1,*, Qiaoming Zhi6, Ze-Kuan Xu7, Rong Wang1, Wen-Jie Wang1, Yang Zong7,8, Zeng-Liang Li7, Yadi Wu9,11, Binhua P. Zhou10,11, Kai Chen1, Min Tao1,12,13,14, Wei Li1,14

1Departments of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China

2Departments of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China

3Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China

4Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, the First Affiliated Hospital of Soochow University, Suzhou, China

5Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

6Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China

7Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

8Department of General Surgery, the Changshu No.1 People’s Hospital, Changshu, China

9Departments of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA

10Departments of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

11Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

12Jiangsu Institute of Clinical Immunology, Suzhou, China

13Institute of Medical Biotechnology, Soochow University, Suzhou, China

14PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China

*These authors have contributed equally to this work

Correspondence to:

Wei Li, e-mail: liwei10@suda.edu.cn

Min Tao, e-mail: mtao@medmail.com.cn; e-mail: taomin@suda.edu.cn

Keywords: PP2A, G2/M cell cycle arrest, JNK, CDK1, Sp1

Received: January 14, 2015     Accepted: May 14, 2015     Published: May 25, 2015

ABSTRACT

Protein phosphatase 2A (PP2A) plays an important role in the control of the cell cycle. We previously reported that the PP2A inhibitors, cantharidin and okadaic acid (OA), efficiently repressed the growth of cancer cells. In the present study, we found that PP2A inhibitors arrested the cell cycle at the G2 phase through a mechanism that was dependent on the JNK pathway. Microarrays further showed that PP2A inhibitors induced expression changes in multiple genes that participate in cell cycle transition. To verify whether these expression changes were executed in a PP2A-dependent manner, we targeted the PP2A catalytic subunit (PP2Ac) using siRNA and evaluated gene expression with a microarray. After the cross comparison of these microarray data, we identified that CDK1 was potentially the same target when treated with either PP2A inhibitors or PP2Ac siRNA. In addition, we found that the down-regulation of CDK1 occurred in a JNK-dependent manner. Luciferase reporter gene assays demonstrated that repression of the transcription of CDK1 was executed through the JNK-dependent activation of the Sp1 transcription factor. By constructing deletion mutants of the CDK1 promoter and by using ChIP assays, we identified an element in the CDK1 promoter that responded to the JNK/Sp1 pathway after stimulation with PP2A inhibitors. Cantharidin and OA also up-regulated the expression of p21, an inhibitor of CDK1, via autophagy rather than PP2A/JNK pathway. Thus, this present study found that the PP2A/JNK/Sp1/CDK1 pathway and the autophagy/p21 pathway participated in G2/M cell cycle arrest triggered by PP2A inhibitors.


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