Dataset Information

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

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.

SUBMITTER: Qiao L

PROVIDER: S-EPMC5964113 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

Qiao Lijun L Zheng Jingyi J Tian Yonghao Y Zhang Qishu Q Wang Xiao X Chen Jason J JJ Zhang Weifang W

Cell death & disease 20180522 6

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 ...[more]

PMID: 29789527

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Project description:UnlabelledThe E7 oncoprotein of the high-risk human papillomavirus (HPV) plays a major role in HPV-induced carcinogenesis. E7 abrogates the G1 cell cycle checkpoint and induces genomic instability, but the mechanism is not fully understood. In this study, we performed RNA sequencing (RNA-seq) to characterize the transcriptional profile of keratinocytes expressing HPV 16 (HPV-16) E7. At the transcriptome level, 236 genes were differentially expressed between E7 and vector control cells. A subset of the differentially expressed genes, most of them novel to E7-expressing cells, was further confirmed by real-time PCR. Of interest, the activities of multiple transcription factors were altered in E7-expressing cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were investigated. The upregulated genes were enriched in cell cycle and DNA replication, as well as in the DNA metabolic process, transcription, DNA damage, DNA repair, and nucleotide metabolism. Specifically, we focused our studies on the gene encoding WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein), one of the genes that was upregulated in E7-expressing cells. WDHD1 is a component of the replisome that regulates DNA replication. Recent studies suggest that WDHD1 may also function as a DNA replication initiation factor as well as a G1 checkpoint regulator. We found that in E7-expressing cells, the steady-state level of WDHD1 protein was increased along with the half-life. Moreover, downregulation of WDHD1 reduced E7-induced G1 checkpoint abrogation and rereplication, demonstrating a novel function for WDHD1. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications.ImportanceThe high-risk HPV types induce cervical cancer and encode an E7 oncoprotein that plays a major role in HPV-induced carcinogenesis. However, the mechanism by which E7 induces carcinogenesis is not fully understood; specific anti-HPV agents are not available. In this study, we performed RNA-seq to characterize transcriptional profiling of keratinocytes expressing HPV-16 E7 and identified more than 200 genes that were differentially expressed between E7 and vector control cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were identified. Significantly, the WDHD1 gene, one of the genes that is upregulated in E7-expressing cells, was found to play an important role in E7-induced G1 checkpoint abrogation and rereplication. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications.

Dataset Information

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

Publications

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

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