Abstract
Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase and plays key roles in nucleo-cytoplasmic transport, mitosis, and nuclear envelope assembly. RCC1 is known to be a critical cell cycle regulator whose loss causes G1 phase arrest, but the molecular basis for this regulation is poorly understood. Furthermore, little is known about the relationship between RCC1 and carcinomas. Human papillomavirus (HPV) infection is highly associated with the development of cervical cancer. The expression and function of RCC1 in HPV-related cervical cancer and cell cycle regulation have not yet been explored. In this study, we first observed that RCC1 immunostaining was mildly increased in cervical cancer tissues and significantly upregulated in HPV E7-expressing cells; this localization was primarily nuclear. We showed that the transcription factor c-Jun transcriptionally upregulates RCC1 via a direct interaction with the RCC1 promoter. Moreover, siRNA-mediated knockdown of RCC1 inhibited G1/S cell cycle progression and DNA synthesis, while overexpression of RCC1 abrogated the G1 checkpoint. RCC1 knockdown downregulated the protein levels of the transcription factor E2F1, especially nuclear E2F1, by promoting its degradation in HPV E7-expressing cells. Overexpression of E2F1 rescued RCC1 knockdown-mediated inhibition of G1/S progression. Additionally, we showed that cyclin-dependent kinase 1 (Cdk1), a known target of E2F1, is involved in G1 checkpoint regulation, as Cdk1 knockdown hindered G1/S progression, while Cdk1 overexpression rescued RCC1 knockdown-mediated effect on G1 cell cycle progression. Furthermore, RCC1 knockdown reduced HPV E7 protein levels, which may in turn downregulate E2F1. Our study explores the function of RCC1 in G1/S cell cycle progression and suggests that RCC1 may be involved in HPV E7-mediated genomic instability.
Highlights
Cervical cancer is one of the most common malignancies in females worldwide[1] and is commonly associated with high-risk human papillomavirus (HR-Human papillomavirus (HPV)) infection[2,3]
We found that Regulator of chromatin condensation 1 (RCC1) mRNA expression was upregulated in cervical cancer tissues and cell lines, including SiHa and HeLa, in comparison with normal cervical epithelium (Fig. 1a,b)
We first showed that RCC1 was upregulated by c-Jun in both cervical cancer tissues and HPV-16 E7-expressing cells
Summary
Cervical cancer is one of the most common malignancies in females worldwide[1] and is commonly associated with high-risk human papillomavirus (HR-HPV) infection[2,3]. The HPV oncogenic proteins E6 and E7 bind to and degrade tumor suppressor p53 and retinoblastoma (pRb), respectively, regulating many key cellular processes such as proliferation and Official journal of the Cell Death Differentiation Association. High-risk HPV (such as HPV-16, 18 etc.), E7 protein, which is consistently expressed in cervical cancer and possesses the major transforming activity, abrogates cell cycle checkpoints and induces genomic instability[6]. Numerous E7 interacting proteins have been identified, there are still many unknown proteins that may be involved in E7-mediated cell cycle regulation and transformation. RCC1 has been shown to be a critical cell cycle regulator and a component of a GTPase switch that monitors the progress of DNA synthesis and couples the completion of DNA synthesis to the onset of mitosis[9,10,11,12]. RCC1 is further involved in nucleo-cytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly following mitosis[13,14]
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