Is Brca-Associated Protein (Bap1) A New Drug
Target to Combat Metastatic Uveal Melanoma?
Abigail R Bland and Rhonda J Rosengren*
Department of Pharmacology and Toxicology, University of Otago, New Zealand
Submission: August 17, 2018; Published: September 10, 2018
*Corresponding author: Rhonda J Rosengren, Department of Pharmacology and Toxicology, 18 Frederick Street, University of Otago, Dunedin, New Zealand, 9016.
How to cite this article: Abigail R B, Rhonda J R. Is Brca-Associated Protein (Bap1) A New Drug Target to Combat Metastatic Uveal Melanoma?. Open
Acc J of Toxicol. 2018;3(4): 555619. DOI: 10.19080/OAJT.2018.03.555619.
This is a review discussing the role of BRCA -associated protein 1 in the development of metastatic uveal melanoma. There is recent in vitro and in vivo evidence to suggest that BRCA-associated protein 1 could be a potential drug target to increase the survival in patients who develop metastatic uveal melanoma. Evidence for the utility of BRCA-associated protein 1 target treatments will be discussed.
Uveal melanoma is a malignant cancer of the eye found primarily in Caucasian adults with 2-8 million cases reported per year . This type of malignancy is found in the iris, choroid or the ciliary body of the eye and ciliary body melanoma has the worst prognosis, while iris melanoma has the best [2,3]. When the tumor is controlled locally survival is high [4,5]. However, systemic metastasis within 5 years of diagnosis occurs in 40-50% of all patients, leading to death in approximately 30% of patients. The liver is the primary site of metastasis and the median survival of patients who develop liver metastasis is 5-6 months, irrespective of their treatment . Furthermore, the overall mortality rate in all uveal melanoma patients is 62% and 90% within 5 and 15 years, post diagnosis, respectively .
Cytogenetic features can also play a role in the prognosis of uveal melanoma where abnormalities in chromosome 1,3,6 and 8 can result in a poor prognosis. This includes whole or partial deletion of chromosome 3, the gain of the long arm of chromosomes 6 and 8 and the loss of the short arm of chromosome 1 . Typical cutaneous melanomas are characterized by mutations in genes such as BRAF, NRAS and NF1, however, uveal melanoma is usually associated with other mutations. These include BRCA-associated-protein-1 (BAP1), GNA11, GNAQ, SF3B1 and EIF1AX . The BAP1 protein is a common germline mutation that is inherited within families.
Non-truncating and truncating mutations in the BAP1 gene have been identified in 18 to 45% of uveal melanoma tumors [7-9]. In a large -scale retrospective study, 4.9% of patients presented with a BAP1 mutation and they also had larger tumors (15.9 vs. 12.3mm, p< 0.01) and a greater occurrence of metastasis (71.4% vs. 18%, p<0.01) compared to those who did not present with a mutation . Furthermore, downstream signaling of BAP1 was lost in cancer due to either the loss of BAP1 in the nucleus (due to a BAP1 mutation, loss of heterozygosity) or due to the localization in the cytoplasm, where it is unable to produce its tumor suppressing activity . Moreover, a Kaplan-Meier analysis of 60 patients showed that the presence of a BAP1 mutation or the absence of BAP1 (through chromosome 3 monosomy) were both significantly associated with a reduction in overall survival . Similar findings were reported, as BAP1 mutations were associated with a significant decrease in progression free survival when compared to wild type tumors (43.2 vs. 94 months, respectively, p<0.01) . Thus, BAP1 mutations were frequently associated with highly metastatic uveal melanoma tumors and therefore, downstream pathways could be considered potential targets.
BAP1 depletion is associated with aggressive metastatic
uveal melanoma tumors, but the exact mechanism by which
BAP1 knockdown increases metastasis is unknown . It has
been hypothesized  that in BAP1 depleted cancers the cell
cycle has become unregulated and although there is no increase
in cell proliferation, the tumor could be the result of a delayed
but permissive G1/S checkpoint. This would allow damaged
and cancerous cells to enter and progress through the cell
cycle instead of undergoing apoptosis. Cell cycle regulation is
vital for ensuring that damaged cells do not multiply, and this
is controlled by many transcription factors and proteins. One
such transcription factor is E2F1, which promotes cell cycle
progression through its involvement in the G1-S phase transition
. Host cell factor 1 (HCF-1), a chromatin-associated protein
that is known to interact with BAP1 [17-19], recruits histone
methyltransferases to the E2F1 promoter and thus enables
transcription of E2F1 target genes.
However, ubiquitination of HCF-1 inhibit its activity on E2F1
and prevents cell cycle progression. It is thought that BAP1 can
deubiquitinate HCF-1 preventing HCF-1 inhibition and therefore,
could potentially indirectly promote cell cycle activation .
Furthermore, others have claimed that dysregulation of the cell
cycle, through a disruption in E2F regulation, could be involved in
the development of uveal melanoma . This was supported by
research that showed that, in BAP1 depleted OCM1 and OM431
human uveal melanoma cells, all E2F1 target genes (p107, SKP2,
Cyclin D and Cyclin E among others) were significantly downregulated
. Thus, BAP1 regulated E2F1 and had an indirect
effect on the regulation of genes expressed during the S phase.
The effect of BAP1 knockdown on growth and migration was also
examined. Cell migration was significantly reduced in the cells
with knockdown of BAP1, which suggested that BAP1 may also
play a role in the regulation of cell migration -associated genes.
BAP1 depletion was also associated with a significant decrease
in the number of soft agar colonies in both OCM1 and OM431
cell lines and in OCM1 cells with BAP1 knocked down there was
a significantly slower cell cycle progression and an arrest of cells
in the S phase .
Dysregulation of the cell cycle is currently the hypothesized
theory for the development of BAP1 depleteduveal melanoma
tumors. To examine this in an in vivo model, NOD- SCID mice
were injected with BAP1 deficient or control uveal melanoma
cells (OCM1A), which formed xenograft tumors. The results
showed that there was a 3-fold decrease in tumor volume
in BAP1 knockdown mice compared to mice bearing control
xenografts . Furthermore, following cell injection via the
tail vein, OCM1A cells with BAP1 knockdown elicited 2-fold less
metastasis to the lungs and 1.5-fold less to the liver compared to
control mice. The group then examined melanocytic properties
in BAP1 depleted uveal melanoma cells. With BAP1 depletion,
the cells had morphological changes where there were fewer
dendritic aborizations and significantly less differentiated
spindle morphology . The authors concluded that uveal
melanoma cells with BAP1 depletion were undergoing a loss
of cell identity, however, it remains unknown how this leads
to metastasis and an aggressive cancer. It may be due to the
disruption of genetic and epigenetic changes that usually prevent
the melanocytes from migrating towards distal sites following
the loss of cell identity. However, to test this hypothesis a BAP1
knockout animal model needs to be developed to model the
metastasis of the tumor cells from the eye.
Uveal melanoma is a malignant cancer found in the eye and
effects approximately 2-8 million people worldwide annually.
When the melanoma is associated with metastasis, the prognosis
is poor with a high mortality rate. Researchers have begun to
examine potential targets in metastatic uveal melanoma to
improve the overall prognosis. One such target is BAP1 which has
been identified in approximately 18-45% of cases. Importantly,
BAP1 loss led to the dysregulation of the cell cycle, a decrease in
the volume of uveal melanoma xenograft tumors and a decrease
in metastases to the liver and lungs. Therefore, BAP1 or its
downstream proteins could prove to be a future drug target.
Thus, future studies should further examine mechanism(s) of
BAP1 loss and potential BAP1-mediated treatments in uveal