Cancer cells acquire mutations that allow them to reactivate early programs that allow them to metastasize throughout the body. In a paper published in the journal Science Advances, researchers at Sylvester Comprehensive Cancer Center, and the nation's No. 1 ranked Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine have identified a master switch – the enzyme Bap1 – that plays a role in early fetal development and cancers such as uveal melanoma.

“Bap1 appears to be regulating cellular identity,” said J. William Harbour, M.D., professor of ophthalmology and director of the Ocular Oncology Service at Bascom Palmer. Dr. Harbour holds the Mark J. Daily Chair in Ophthalmology and leads Sylvester’s Eye Cancer Site Disease Group. “When Bap1 is lost, cancer cells lose their identity and stop obeying the rules that the normal cell type follows. In uveal melanoma, the tumor cells missing Bap1 don’t resemble melanocytes anymore, and they become more primitive. They stop obeying the signals saying stay put.”

Bap1 loss has also been implicated in renal cell carcinomas, mesotheliomas, and other cancers, but there has been little agreement on how Bap1 works. To better understand Bap1’s function, Dr. Harbour’s team studied its role during development. They employed Xenopus frogs, which are commonly used to study early vertebrate development. They found that removing Bap1 caused major problems during development, especially in the neural crest lineage, which gives rise to uveal melanoma.

“When neural crest cells lack Bap1, they make the switch to differentiated melanocytes poorly,” said Dr. Harbour. “It’s similar to what we see in human uveal melanoma.”

Further study showed Bap1 regulates H3K27 acetylation by inhibiting HDAC4 at differentiation genes that fail to turn on when Bap1 is missing.

“Bap1 is a master switch that causes pluripotent cells to differentiate,” said Dr. Harbour.

Loss of Bap1 in cancer cells allows them to differentiate and acquire primitive capabilities that result in metastasis.

Dr. Harbour’s group is now pursuing potential therapies, such as HDAC4 inhibitors.

“We have identified a potent HDAC4 inhibitor that we’d like to move into the clinic.”

Dr. Harbour’s work on Bap1 was supported by the U.S. Department of Defense and the National Cancer Institute.