Cancer cells remember things they shouldn’t. During development, stem and progenitor cells move freely through the body as they differentiate into heart, brain, liver, eyes. But after humans are born, that process should stop. Cells shouldn’t travel or change anymore; they should stay put and do their jobs.
Sometimes, things happen to cancer cells that allow them to remember their early programming and start migrating again, metastasizing throughout the body. However, the mechanisms driving that reversion aren’t always clear.
But now, in a paper published in the journal Science Advances, researchers at Sylvester Comprehensive Cancer Center, which recently received National Cancer Institute designation, 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 both early fetal development and cancers such as uveal melanoma, the most common primary eye cancer.
“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. “In cancers in which Bap1 is lost, cells lose their identity and stop obeying the rules that all cell types are supposed to obey. In uveal melanoma, the tumor cells don’t resemble melanocytes anymore, they become more primitive and express stem cell-like genes. They become de-differentiated and stop obeying the signals in the eye saying stay put.”
In addition to uveal melanoma, Bap1 loss has been implicated in renal cell carcinomas, mesotheliomas and other cancers. The protein acts as a tumor suppressor, but there has been little agreement on how Bap1 accomplishes this. Some think the protein might be associated with cell cycle regulation or DNA damage repair. Others believe it may play a role in apoptosis.
To better understand the protein’s mechanisms, Dr. Harbour’s team wanted to see it in action during development. Unfortunately, that’s a tricky proposition, as Bap1 knockout mice (a genetically modified mouse missing Bap1) die in utero. Instead, the lab employed Xenopus frogs, which are commonly used to study early vertebrate development, paying close attention to the neural crest lineage, which gives rise to the cells that become malignant in uveal melanoma. They found that removing Bap1 created abnormal cells and stunted development.
“When cells giving rise to neural crest lack Bap1, they make the switch from progenitor cells to differentiated melanocytes poorly,” said Dr. Harbour. “It’s similar to what we see in human uveal melanoma.”
Further study showed Bap1 partners with ASXL proteins, forming an enzyme complex that removes ubiquitin from histones to regulate gene expression. The enzymes that catalyze H3K27 acetylation appear to play a critical role during development, activating genes that trigger differentiation in various tissues, thereby switching from pluripotency to differentiation.
“Bap1 is a master switch that moves these cells from a pluripotent lineage to a differentiating lineage,” said Dr. Harbour.
But without Bap1, that switch doesn’t get turned on. A particularly important repression target for Bap1 is HDAC4. Without Bap1, HDAC4 remains active and keeps differentiation genes from turning on.
These findings offer great insights into how Bap1 influences uveal melanoma and other cancers. Though losing the enzyme does not initiate malignancy, it allows the cancer to flourish.
“Even if you have a cancer-initiating mutation in a gene such as GNAQ or BRAF, the cells still essentially obey the rules about staying put in their tissue of origin,” said Dr. Harbour. “But when Bap1 is mutated, all bets are off. The tumor cells disobey the rules and change their behavior and move to other parts of the body.”
However, by carefully dissecting the Bap1 pathway, Dr. Harbour’s group may have outlined a potential therapeutic strategy. Bap1 inhibits HDAC4 and there are HDAC inhibitors available – and Dr. Harbour’s team is testing even more.
“We’re actively performing high throughput drug screenings and looking at preclinical models with some promising new HDAC inhibitors 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.