A Novel Role for BAP1 in Development and Tumor Suppression

DAWN OWENS; JEFFIM KUZNETSOV; AGÜERO, TRISTAN; KURTENBACH, STEFAN; MATTHEW G. FIELD; DURANTE, MICHAEL A.; MARY LOU KING; WILLIAM HARBOUR

Atlanta

Congreso; American Association of Cancer Research Annual Meeting; 2019

Uveal melanoma (UM) is the second most common form of melanoma and one of the most deadly types of cancer. Recent discoveries in our laboratory and others have led to a deeper understanding of the driver mutations UM. The initiating mutation that is present in virtually all UM occurs in one of four genes in the Gaq signaling pathway (the ?Gaq? mutations) and result in sustained activation of proliferative signals. A second mutation occurs later in one of three genes ? BAP1, SF3B1 or EIF1AX (the ?BSE? mutations), which determines metastatic risk ? BAP1 (high risk), SF3B1 (intermediate risk) or EIF1AX (low risk). Surprisingly, we recently discovered that the Gaq mutation and the subsequent BSE mutation occur very close in molecular time. This work suggests that Gaq mutations may cause epigenetic changes that predispose to BSE mutations. We have shown that BAP1-mutant UMs exhibit a de-differentiation and stem-cell like phenotype, suggesting that BAP1 may normally regulate differentiation programs during embryonic development. Consistent with this possibility, BAP1 loss in mouse is embryonic lethal. To study the role of BAP1 in early vertebrate development, therefore, we chose Xenopus laevis (African clawed frog), a widely used model for studying gene function during development. We found that targeted depletion of the Xenopus BAP1 protein (xBap1) causes a striking developmental phenotype affecting multiple germ layers, and that this phenotype is associated with disruption of super enhancers around differentiation genes that are normally maintained by BAP1. Taken together, these studies suggest that loss of BAP1 promotes tumor progression and metastasis, at least in part, by disrupting tightly controlled differentiation programs that govern cell identity. These findings may nominate new therapeutic targets in BAP1-mutant cancers.