Over-expression of CHAF1A in Epithelial Ovarian Cancer can promote cell proliferation and inhibit cell apoptosis

https://doi.org/10.1016/j.bbrc.2017.03.026Get rights and content

Highlights

  • CHAF1A expression is significantly elevated in EOC.

  • CHAF1A is associated with poor clinical outcomes in EOC.

  • Knockdown CHAF1A inhibits proliferation, induces G0/G1 phase arrest and promotes apoptosis in EOC.

Abstract

Chromatin Assembly Factor 1, subunit A (CHAF1A) can regulate cell proliferation, DNA repair and epigenetic changes in embryonic stem cells and it has been reported that over-expression of CHAF1A is associated with several human diseases including cancer. However, the expression and function of CHAF1A in Epithelial Ovarian Cancer (EOC) are rarely reported at present. In this study, we found that the positive staining of CHAF1A in EOC was higher than that in normal tissues and over-expression of CHAF1A was strongly associated with cancer stage and lymph node metastasis. Knockdown of CHAF1A by siRNA in EOC inhibited cell proliferation, reduced colony formation, caused G0/G1 phase arrest and promoted cell apoptosis. Taken together, the high expression of CHAF1A promotes cell proliferation and inhibits cell apoptosis and CHAF1A may be developed as a prognosis biomarker and potential therapeutic target of EOC.

Introduction

Ovarian cancer,90% is Epithelial Ovarian Cancer (EOC), is a malignant tumor with the highest death rate in female reproductive system, due to the lack of clear and effective diagnostic methods in identifying early stage disease [1]. The majority of patients are diagnosed with advanced disease, and the five-year survival rate for EOC is about 30% [2]. The standard treatment of advanced EOC includes primary cytoreductive surgery followed by chemotherapy aiming at optimal residual tumor volumes. However, shortage of suitable biologic markers, limitations in the timely screening methods, early metastasis and resistance to chemotherapeutic drugs become the major obstacles for EOC therapy.

In eukaryotic cells, the genomic DNA is assembled into chromatin [3]. Chromatin Assembly Factor 1, subunit A(CHAF1A)which is also called P150, is the subunit of Chromatin Assembly Factor-1 (CAF-1) which also comprised of P48 and P60, as a member of histone chaperone that participates in the deposition of histone H3 and H4 to the newly synthesized DNA [4]. Its functions include: (1) deposit the histone and assemble the chromatin; (2) regulate H3 lysine 9 trimethylation; (3) assist DNA repair [5]. Present study has indicated that dysregulation of the chromatin assembly might contribute to development of tumors [6] and failure of DNA damage repair might result in genomic instability [7], affecting the normal transmission of genetic material, changing the behavior of cells, and correlated with development, proliferation, chemotherapy resistance of ovarian cancer, which can be a hallmark of tumor development and a therapeutic target [8]. Recent studies have found that CHAF1A can promote the metastasis and inhibit the differentiation in vitro and in vivo model of neuroblastoma. High expression of CHAF1A leads to an undifferentiated phenotype and leads to a reduction in overall survival rate, as well as a change to the oncogenic signaling pathways and the glycolytic pathway [9]. Many studies have shown that CHAF1A is also highly expressed in many tumors such as breast cancer, colon cancer and cervical cancer, which can be used as a potential marker to judge the prognosis of tumor patients and a target of the treatment of tumor [10]. As a cancer driver gene, dysfunction of CHAF1A can result in increased cell proliferation, cell death, and genomic instability and eventually form a more aggressive cancer phenotype [11]. However, the expression and biological function of CHAF1A in EOC remains largely unidentified.

In the current study, we detected the expression level of CHAF1A in normal ovarian and EOC tissues by immunohistochemistry and analyzed the relationship between CHAF1A expression and clinicopathological characteristics of EOC. We used siRNA to interfere with CHAF1A, then evaluated the role of CHAF1A in proliferation and apoptosis in EOC cells. In conclusion, we found that knockdown of CHAF1A in EOC could suppress proliferation and promote apoptosis and CHAF1A promise to be a new biological marker for EOC.

Section snippets

Patients and tissues samples

We obtained 13 normal and 40 EOC tissue samples and all patients were clinically and histopathologically diagnosed between June 2008 and June 2009. We obtained written and informed consent from all patients. This study was approved by the Institutional Research Ethics Committee of Shanghai Jiaotong University Affiliated First People's Hospital.

Cell lines and cultures

Normal ovarian epithelial cell line: Moody, human ovarian tumor cell lines:SKOV3, Hey,HO8910-PM, HO8910 and ES-2 were cultured in RPMI-1640 medium

CHAF1A is overexpressed in EOC

In order to evaluate the expression of CHAF1A in EOC, 40 paraffin-embedded human EOC samples and 13 paraffin-embedded human normal ovarian tissues were detected by immunohistochemical staining. CHAF1A is mainly expressed in EOC, whereas CHAF1A staining was minimally detectable in normal ovarian epithelium (Fig. 1A; Table 2). Based on cell immunofluorescence staining, CHAF1A predominantly localized positive in the nucleus of EOC cells (Fig. 1B). CHAF1A protein expression were found to be

Discussion

Despite early diagnosis and advances in chemotherapy, EOC remains the leading cause of death from gynecological malignancy with mortality rates decreasing only slightly over the past few years [13]. Tumors are characterized by excessive proliferation, which is accompanied by the activation of many oncogenes and the inactivation of many suppressor genes caused by the dysfunction of chromatin assembly and DNA damage repair, and often present the expression profile of embryonic cells [14]. Hanahan

Conflict of interest

No Conflict of Interest.

Acknowledgments

This study was supported by Shanghai First People’s Hospital, Shanghai Jiao Tong University, China. This study was sponsored by National Natural Science Foundation of China (NSFC No. 81172478).

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    Dandan Xia and Xiaoming Yang contributed equally to this work.

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