ESRP1 Induces Cervical Cancer Cell G1-Phase Arrest Via Regulating Cyclin A2 mRNA Stability.

Zhi-Hong Chen,Ya-Jie Jing,Xiu-Zhen Su,Zai-Shu Jin,Zhu Li,Jian-Bo Yu,Ting-Ting He

doi:10.3390/ijms20153705

Abstract

Accumulating evidence indicates that epithelial splicing regulatory protein 1 (ESRP1) can inhibit the epithelial-to-mesenchymal transition (EMT), thus playing a central role in regulating the metastatic progression of tumors. However, it is still not clear whether ESRP1 directly influences the cell cycle, or what the possible underlying molecular mechanisms are. In this study, we showed that ESRP1 protein levels were significantly correlated with the Ki-67 proliferative index (r = −0.521; p < 0.01), and that ESRP1 overexpression can significantly inhibit cervical carcinoma cell proliferation and induced G1-phase arrest by downregulating cyclin A2 expression. Importantly, ESRP1 can bind to GGUGGU sequence in the 3′UTR of the cyclin A2 mRNA, and ESRP1 overexpression significantly decreases the stability of the cyclin A2 mRNA. In addition, our experimental results confirm that ESRP1 overexpression results in enhanced CDC20 expression, which is known to be responsible for cyclin A2 degradation. This study provides the first evidence that ESRP1 overexpression induces G1-phase cell cycle arrest via reducing the stability of the cyclin A2 mRNA, and inhibits cervical carcinoma cell proliferation. The findings suggest that the ESRP1/cyclin A2 regulatory axis may be essential as a regulator of cell proliferation, and may thus represent an attractive target for cervical cancer prevention and treatment.

Highlights

Cervical cancer (CC) is among the most frequently encountered forms of gynecological malignancies, resulting from the abnormal malignant proliferation of cervical epithelial cells
We found that FLAG-epithelial splicing regulatory protein 1 (ESRP1) bound the cyclin A2 3′UTR, while no control binding was observed (Figure 4D). These results demonstrate that ESRP1 regulates cyclin A2 mRNA stability via interacting with the 3′UTR of Itnhti.sJ.mMRol.NSAci
We found that ESRP1 overexpression significantly decreased CYCA-Luc luciferase activity, and we further found that that ESRP1 overexpression led to a downregulation of the expression of cyclin A2, and an induction of G1-phase arrest in HeLa cells

Summary

Introduction

Cervical cancer (CC) is among the most frequently encountered forms of gynecological malignancies, resulting from the abnormal malignant proliferation of cervical epithelial cells. The cell cycle governs cellular proliferation, progressing through the G1, S, G2, and M -phases in a carefully regulated and ordered fashion [3]. Cell cycle checkpoints exist to help regulate the order of cell cycle transitions, and to guarantee that DNA is properly replicated and cells are prepared to divide, with G1, G2, and metaphase (M) or spindle checkpoints [4]. In the mammalian cell cycle, the G1 checkpoint is referred to as a restriction point (R-point), as it represents the checkpoint after which cells commit to enter into the S-phase, leading to cell cycle completion [5,6]. When cells fail to pass through the R-point, the G1-to-S-phase transition fails to occur, leading to G1-phase arrest, and many studies have confirmed that cyclin A2, a key cell cycle regulator, initiates and controls DNA replication, which is crucial for DNA synthesis and for the G1/S-phase transition. Among the most common types of cancer, cyclin A2 is considered to be a major factor controlling cell proliferation, and increased expression of cyclin A2 protein has been observed in many types of cancer such as breast, cervical, liver, and lung cancer, with only limited expression in normal tissues [4,7,8]

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