Melanomas, the deadliest form of skin cancer, can adopt multiple transcriptional states. Our understanding of the epigenetic mechanisms underlying various cell states must be improved, hindering our capacity to control melanoma heterogeneity.
Subgroups of cells with varying gene expression patterns and capacities to penetrate surrounding tissues and withstand anticancer treatments make up melanoma tumors. The role of these various melanoma subgroups in the initiation and spread of tumors is unknown.
Scientists at Moffitt Cancer Center‘s Donald A. Adam Melanoma and Skin Cancer Center of Excellence are working to understand better what drives melanoma brain metastasis. They have published a study identifying a cell signaling pathway that controls the metastatic spread of melanoma cells to the brain.
Previously, scientists found that a protein called HDAC8 controls resistance to BRAF and MEK inhibitors commonly used to treat melanoma. Gene expression patterns are altered when HDAC8 removes acetyl groups, a chemical modification, from other proteins. Scientists hypothesized that HDAC8 might also be important in controlling the subgroups of melanoma cells’ gene expression patterns.
In experiments, scientists demonstrated that when melanoma cells are under stress—such as when exposed to low oxygen levels, UV light, or BRAF/MEK inhibitor therapy—HDAC8 activation increases their survival. In addition, HDAC8 activity altered the melanoma cells’ gene expression pattern and gave rise to traits typical of cell subgroups that can infiltrate and migrate into nearby areas.
From experiments, scientists found that increased HDAC8 expression and activity increase the ability of melanoma cells to metastasize to the brain. However, there was no significant impact on the number of metastatic tumors in other organs, such as the liver or lung.
After delving deeper into the molecular mechanisms of HDAC8-induced brain metastasis, scientists found that HDAC8 altered the protein EP300 chemically, developing invasive features in cells. Scientists demonstrated that higher expression of EP300 reduced cell invasion and made melanoma cells more susceptible to cell death, confirming the significance of EP300 to melanoma brain metastases.
Keiran Smalley, Ph.D., lead study author and director of Moffitt’s Melanoma and Skin Cancer Center of Excellence, said, “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. Our work provides the first evidence that stress-induced HDAC8 regulates an invasive melanoma cell state, leading to increased brain metastasis.”
Journal Reference:
- Emmons, M.F., Bennett, R.L., Riva, A. et al. HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis. Nat Commun 14, 7759 (2023). DOI: 10.1038/s41467-023-43519-1