Metastasized melanoma cells in the brain mark the end stages of the cancer’s progression. The process by which the cells get to the brain is a complex one but a new study has identified one of the signaling pathways that regulates the movement of melanoma cells. Details of the study, which was done by scientists at Moffitt Cancer Center, are published in Nature Communications in a paper titled, “HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis.”

The findings build on previous studies that identified a regulatory role for a protein called HDAC8 in melanoma. The protein regulates resistance to BRAF and MEK inhibitors which are commonly used to treat skin cancers. Specifically it removes protein acetyl groups, altering the gene expression patterns of cells. Given its profile as a deacetylase, the researchers suspected that HDAC8 might play a role in regulating the varied gene expression patterns observed in groups of melanoma cells—up to four different expression states have been identified. These patterns of gene expression have an effect on the cells’ ability to invade surrounding tissues and survive treatment. 

In the context of melanoma, HDAC8’s effect on cells’ trascriptional activity is activated by stress. For the study, the researchers assessed HDAC8 activity under several stress conditions including low oxygen, UV radiation, and the presence of melanoma drugs. Its activity in these conditions increased melanoma cell survival, and changed the gene expression patterns of the tumor cells enabling them to migrate into surrounding tissue and reach the brain. This makes sense because their data showed that many of the genes upregulated by HDAC8 are involved in cytoskeletal rearrangement. 

Digging deeper, the team discovered that HDAC8 deactivates the EP300 protein and that this action is what allows the tumor cells to develop their invasive characteristics. They confirmed this with tests that showed that when EP300 expression was up, the melanoma cells were less invasive and more sensitive to inhibitor-based therapies. In contrast, “inhibition of EP300 increases melanoma cell invasion, resistance to stress, and increases melanoma brain metastasis development,” the researchers wrote. Finally, evidence from the melanoma cell lines suggests that HDAC8’s activity did not significantly impact melanoma’s metastasis to other organs like the liver, lungs, ovaries, and spleen. 

“Our work provides the first evidence that stress induced HDAC8 is a regulator of an invasive melanoma cell state that leads to increased brain metastasis,” said Keiran Smalley, PhD, lead author and director of Moffitt’s Melanoma and Skin Cancer Center of Excellence. The findings also suggest that drugs that target the HDAC8 and EP300 pathways “may inhibit brain metastasis.” 

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