Abstract
BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that has long been considered to be a tumor suppressor in various tumors, including renal cell carcinoma, uveal melanoma, mesothelioma, and cutaneous melanoma. However, the involvement of BAP1 in the progression of prostate cancer has not been studied until recently. Herein, we investigated the tumor promoting function of BAP1 in the context of prostate cancer. Analysis of The Cancer Genome Atlas (TCGA) data set showed that prostate cancer patients express high levels of BAP1 mRNA. High BAP1 expression is inversely correlated with disease-free survival in patients with prostate cancer. Among the prostate cell lines tested, BAP1 expression was high in tumorigenic and metastatic cell lines, but was low in normal prostate cell line. Knockdown of BAP1 in PC3 or DU145 cells induced mesenchymal-to-epithelial transition (MET). Further, BAP1-knockdown resulted in decreased migration and invasion of PC3 and DU145 cells. Conversely, overexpression of BAP1 in RWPE1, a normal prostate cell line, induced the migratory and invasive properties. Collectively, our findings identified that BAP1 has a tumor promoting function in prostate cancer cells, and suggest that BAP1 can serve as a potential therapeutic target for prostate cancer.
Highlights
BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme, which cleaves ubiquitin (Ub) from substrate proteins, and is subcategorized into ubiquitin C-terminal hydrolases (UCHs) (Fang and Shen, 2017)
On analyzing the data hosted on The Cancer Genome Atlas (TCGA) database, we found that the expression of BAP1 mRNA is increased in the patients with prostate cancer, and that high BAP1 expression is inversely correlated with disease-free survival
We identified that BAP1-knockdown results in the inhibition of migration/invasion and induction of mesenchymal-to-epithelial transition (MET) in prostate cancer cells
Summary
BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme, which cleaves ubiquitin (Ub) from substrate proteins, and is subcategorized into ubiquitin C-terminal hydrolases (UCHs) (Fang and Shen, 2017). Recent investigations suggest that BAP1 functions in various biological processes, including the DNA damage response, transcriptional regulation, chromatin dynamics, and cell cycle regulation. BAP1 is known to assemble multiprotein complexes with numerous cofactors and transcription factors including Ying Yang 1 (YY1) and host cell factor 1 (HCF1) (Yu et al, 2010). Ternary complexes of BAP1 with the forkhead transcription factors FoxK1/K2 and HCF1 have been reported. The catalytic activity of BAP1 is attributed to its repression of FoxK2 target genes (Okino et al, 2015). BRCA1/BARD1 is a RING heterodimer E3 ligase that is involved in the regulation of DNA damage response. BAP1 binding to BARD1 results in inhibition of the E3 ligase activity of BRCA1/BARD1 via the prevention of RING heterodimer formation (Nishikawa et al, 2009).
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