Pre-clinical studies find HDAC8 inhibition of EP300 leads to melanoma cell metastasis to the brain.

More than half of patients with advanced melanoma will see the disease spread to the brain, where it rapidly progresses, often leading to death in only three to four months. Researchers in Moffitt Cancer Center’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence have been working to better understand what drives melanoma brain metastasis.

 In a new study in Nature Communications, they report on the identification of a cell signaling pathway that regulates the metastatic spread of melanoma cells to the brain.

In previous studies, Moffitt researchers determined that the protein HDAC8 regulated resistance to BRAF and MEK inhibitors commonly used to treat melanoma. HDAC8 removes chemical modifications called acetyl groups from other proteins, leading to alterations in gene expression patterns. The Moffitt team hypothesized that HDAC8 may also be involved in the regulation of gene expression patterns of melanoma cell subgroups.

To find out, they performed laboratory experiments and demonstrated that HDAC8 activity increased melanoma cell survival under stress conditions, including low oxygen, UV radiation, and BRAF/MEK inhibitor treatment. HDAC8 activity also changed the gene expression pattern of melanoma cells and caused the cells to develop characteristics associated with cell subgroups that were able to migrate into and invade surrounding sites.

Their pre-clinical experiments found that increased HDAC8 expression and activity enhanced the ability of melanoma cells to metastasize to the brain, while no significant impact was observed in the number of metastatic tumors to other organs, such as the liver or lung. The researchers further investigated the molecular pathways of HDAC8-mediated brain metastasis and discovered that HDAC8 chemically modified the protein EP300, which subsequently caused cells to develop invasive characteristics. The researchers confirmed the importance of EP300 to melanoma brain metastases by showing that increased expression of EP300 decreased cell invasion and caused melanoma cells to be more sensitive to cell death.

“These data show the importance of HDAC8 and EP300 activity to melanoma cell invasion to the brain and suggest that agents that target these pathways may inhibit brain metastasis,” says Keiran Smalley, Ph.D., lead study author and director of Moffitt’s Melanoma and Skin Cancer Center of Excellence, in a news release. “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.”