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Tumor suppressive effects of bromodomain-containing protein 7 (BRD7) in epithelial ovarian carcinoma
Young-Ae Park1, Jeong-Won Lee, Hye-Sun Kim
1Authors' Affiliations: Department of Obstetrics & Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine; and Department of Pathology, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea.
Purpose:
Bromodomain-containing protein 7 (BRD7), which is a subunit of SWI/SNF complex, has been recently suggested as a novel tumor suppressor in several cancers. In this study, we investigated the tumor suppressive effect of BRD7 in epithelial ovarian cancer.
Experimental Design:
We analyzed the expression of BRD7 in human ovarian tissues with real-time PCR. To investigate the functional role of BRD7, we transfected ovarian cancer cells (A2780 and SKOV3) with BRD7 plasmid and checked the cell viability, apoptosis, and invasion. The activities of BRD7 in the signaling pathways associated with carcinogenesis were also tested. In addition, we used the orthotopic mouse model for ovarian cancer to evaluate tumor growth-inhibiting effect by administration of BRD7 plasmid.
Results:
The BRD7 expression was downregulated in the ovarian cancer tissues compared with normal (P < 0.05), high-grade serous cancer exhibited significantly decreased expression of BRD7 compared with low-grade (P < 0.01) serous cancer. Transfection of BRD7 plasmid to A2780 (p53-wild) or SKOV3 (p53-null) ovarian cancer cells showed the tumor suppressive effects assessed by cell viability, apoptosis, and invasion assay and especially significantly decreased tumor weight in orthotopic mouse model (A2780). Moreover, we found that tumor suppressive effects of BRD7 are independent to the presence of p53 activity in ovarian cancer cells. BRD7 negatively regulated β-catenin pathway, resulting in decreased its accumulation in the nucleus.
Conclusions:
These results suggested that BRD7 acts as a tumor suppressor in epithelial ovarian cancers independently of p53 activity, via negative regulation of β-catenin pathway.
Insights
Bromodomain-containing protein 7 (BRD7) suppresses epithelial ovarian cancer by inhibiting the beta-catenin pathway. This tumor suppressor role is independent of p53 activity, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Bromodomain-containing protein 7 (BRD7) is a subunit of the SWI/SNF complex.
- BRD7 has been implicated as a tumor suppressor in various cancers.
- Its role in epithelial ovarian cancer requires further investigation.
Purpose of the Study:
- To investigate the tumor suppressive effect of BRD7 in epithelial ovarian cancer.
- To determine the association between BRD7 expression and clinicopathological features.
- To elucidate the underlying molecular mechanisms of BRD7's action.
Main Methods:
- Real-time PCR to analyze BRD7 expression in human ovarian tissues.
- In vitro assays (cell viability, apoptosis, invasion) using ovarian cancer cell lines transfected with BRD7.
- Orthotopic mouse model to evaluate tumor growth inhibition by BRD7.
- Analysis of BRD7's effect on key signaling pathways, including the beta-catenin pathway.
Main Results:
- BRD7 expression was significantly downregulated in ovarian cancer tissues compared to normal tissues.
- High-grade serous ovarian cancers showed significantly lower BRD7 expression than low-grade cancers.
- BRD7 transfection suppressed cell viability and invasion, and induced apoptosis in ovarian cancer cells, independent of p53 status.
- BRD7 significantly inhibited tumor growth in an orthotopic mouse model.
- BRD7 negatively regulated the beta-catenin pathway by decreasing nuclear accumulation of beta-catenin.
Conclusions:
- BRD7 functions as a tumor suppressor in epithelial ovarian cancer.
- BRD7's tumor-suppressive activity is independent of p53.
- BRD7 exerts its effects through the negative regulation of the beta-catenin pathway.
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