Abstract
Bromodomain testis-specific factor (BRDT) is a member of the bromodomain and extra-terminal (BET) family proteins. Its expression and potential functions in ovarian cancer were examined. We show that BRDT is overexpressed in human ovarian cancer tissues and in established (CaOV3)/primary ovarian cancer cells. However, its expression is low in ovarian epithelial tissues and cells. Significantly, shRNA-induced silencing or CRISPR/Cas9-mediated knockout of BRDT inhibited ovarian cancer cell growth, viability, proliferation and migration, and induced significant apoptosis activation. Conversely, exogenous overexpression of BRDT, by a lentiviral construct, augmented CaOV3 cell proliferation and migration. In CaOV3 cells expression of two key BRDT target genes, polo-like kinase 1 (PLK1) and aurora kinase C (AURKC), was downregulated by BRDT shRNA or knockout, but upregulated with BRDT overexpression. In vivo, xenograft tumors-derived from BRDT-knockout CaOV3 cells grew significantly slower than control tumors in severe combined immunodeficient (SCID) mice. Furthermore, intratumoral injection of BRDT shRNA lentivirus potently inhibited the growth of primary ovarian cancer xenografts in SCID mice. Downregulation of PLK1 and AURKC was detected in BRDT-knockout and BRDT-silenced tumor tissues. Collectively, BRDT overexpression promotes ovarian cancer cell progression. Targeting BRDT could be a novel strategy to treat ovarian cancer.
Highlights
Despite significant progresses have been achieved to improve the overall survival of ovarian cancer in past decades, it is still one primary cause of female mortality[1]
Forced Bromodomain testis-specific factor (BRDT) overexpression in CaOV3 cells significantly increased polo-like kinase 1 (PLK1) and aurora kinase C (AURKC) expression (Fig. 6C, D). These results suggest that BRDT is important for PLK1 and AURKC expression in ovarian cancer cells
There were no noticeable signs of apparent toxicity. These results suggest that BRDT-KO significantly inhibited CaOV3 cell growth in vivo
Summary
Despite significant progresses have been achieved to improve the overall survival of ovarian cancer in past decades, it is still one primary cause of female mortality[1]. Because of the significant resistance and recurrence, researchers are focusing on novel oncogenes and cell signaling pathways essential for cancer progression[3,4,5]. BRDT, like other BET family proteins (BRD1–4), epigenetically regulates targeted genes expression through interacting with acetylated lysines[7,8], critical for normal development and disease (cancer) progression[6]. Recent studies have implied that BET family proteins are key oncogenic proteins, being overexpressed in a number of different cancers[7,8]. Inhibitors of BET proteins have displayed promising efficiency against human cancer cells in vitro and in vivo[9,10]
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