BAP1

Official Full Name

BRCA1 associated deubiquitinase 1

Organism

Homo sapiens

GeneID

8314

Background

This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

Synonyms

UBM2; UVM2; KURIS; TPDS1; UCHL2; hucep-6; HUCEP-13;

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Detailed Information

BRCA1-associated protein 1 (BAP1) was originally identified as a protein that interacted with the RING finger domain of the breast cancer susceptibility gene product BRCA1. BAP1 is a deubiquitinating enzyme with ubiquitin carboxy terminal hydrolase (UCH) domain that confers BAP1 its deubiquitinating enzyme activity. BAP1 has been reported to be involved in many cellular processes, such as cell fate determination, stem cell pluripotency and other developmental processes. For example, BAP1 can enhance progression through G1-S checkpoints and subsequently induce cell death by processes similar to apoptosis and necrosis. Furthermore, BAP1 inhibits cell proliferation by deubiquitinating host cell factor-1 (HCF1). In cancer, BAP1 acts as a tumor suppressor and metastasis inhibitor. Overexpression of BAP1 has been shown to inhibit tumor cell expansion in mouse xenografts.

BAP1 and neuroblastoma

Neuroblastoma originates from the sympathetic nervous system and consists of undifferentiated and poorly differentiated neuroblasts arising from different stages of the sympathetic adrenal lineage of neural crest origin. Recent studies have found that decreased expression of BAP1 pro6 promotes survival of neuroblastoma cells, and restoring levels of BAP1 in these cells promotes delays in the S and G2/M phases of the cell cycle, as well as apoptosis. The mechanism that BAP1 induces cell death is mediated through interaction with 14-3-3 proteins. The association between BAP1 and 14-3-3 proteins releases the apoptosis-inducing protein Bax from 14-3-3 and promotes cell death through the intrinsic apoptotic pathway. Xenograft studies have demonstrated that BAP1 expression reduced tumor growth and in vivo progression by reducing the level of pro-survival factors such as Bcl-2, which in turn reduces the survival potential of tumor cells. Patient data analysis confirmed the ﬁnding that high BAP1 mRNA expression associated with better clinical outcomes. In summary, existing studies have revealed a novel mechanism by which BAP1 regulates apoptosis in neuroblastoma cells.

Figure 1. Model of BAP1-induced regulation of cell survival and cell death in neuroblastoma cells. (sime et al. Cell Death and Disease, 2018)

BAP1 and breast cancer

Breast cancer is one of the most common malignancies and seriously affects the health of women worldwide. The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumor growth. In breast cancer cells, KLF5 is stabilized by deubiquitinating enzyme (DUB) BAP1. BAP1 was identified as skeletal KLF5 DUB by DUB's genome-wide RNA library screening. BAP1 interacts directly with KLF5 and stabilizes KLF5 by deubiquitination. KLF5 is located in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be partially rescued by ectopic expression of KLF5. Overall, the current studies not only identify BAP1 as the DUB for KLF5, but also reveal a key mechanism that regulates KLF5 expression in breast cancer. The results suggest that BAP1 may be a potential therapeutic target for breast cancer and other cancers.

BAP1 and MPM

Recently, studies have shown that BAP1 has emerged as a promising biomarker for malignant pleural mesothelioma (MPM). McGregor et al. found BAP1 retention in non-neoplastic mesothelial tissues. Furthermore, BAP1 expression in the spindled mesothelium enabled discrimination of reactive and malignant cells, thus providing a more objective means of distinguishing epithelioid from biphasic morphology compared to histology alone. Despite this, BAP1 staining was patchy in some benign mesothelioma tumors, which raises concerns about the use of BAP1 in small biopsies. Kaplan-Meier analysis showed that BAP1 loss resulted in a significant improvement in overall survival, but this was not significant in the multivariate analysis of histological subtypes. When only epithelial-like cases were analyzed, there was a tendency to increase survival, but it did not reach significance. In conclusion, loss of BAP1 in epithelioid MPM has been shown to be common, which is in turn associated with improved survival, and that it can have additional clinical implications by promoting histological classification.

BAP1 and meningiomas

The clinical course of meningioma patients varies widely. Objective molecular determinants are needed to guide classification and clinical decision making. Recent studies have found that patients with BAP1-negative rhabdoid meningioma had a shorter relapse time than patients with BAP1-retained rhabdoid meningioma. A portion of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, suggesting that striated meningioma may be a precursor to the BAP1 cancer susceptibility syndrome. Rhabdoid-like meningioma with familial and sporadic BAP1 mutations was found to be clinically invasive and required intensive clinical management.

In summary, BAP1 is associated with a multiprotein complex that regulates key cell pathways, including cell cycle, cell differentiation, cell death, and DNA damage responses. However, the role of BAP1 in the development and progression of human cancer remains poorly understood. Therefore, further research on the role of BAP1 in cancer development mechanisms will provide new insights and new directions for the diagnosis and treatment of related cancers.

References:

Yu MC, et al. BAP1 suppresses lung cancer progression and is inhibited by miR-31. Oncotarget, 2016, 7: 12
Sime, et al. BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma. Cell Death and Disease, 2018, 9:458
Qin JY, et al. BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5. Nature Communications, 2015, 6: 8471
Yan L, et al. MiR-125a-5p functions as a tumour suppressor in breast cancer by downregulating BAP1. Journal Of Cellular Biochemistry, 2018, 119(11): 8773-8783
McGregor SM, et al. BAP1 facilitates diagnostic objectivity, classification, and prognostication in malignant pleural mesothelioma. Human Pathology, 2015, 46(11): 1670-1678
Shankar GM, et al. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-Oncology, 2017, 19(4): 535–545

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