Histone Variant Linked to Melanoma Progression

Development and spread of melanoma has been linked to the loss of a specific histone isoform.

Histones are highly alkaline proteins found in eukaryotic cell nuclei, which package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, act as spools around which DNA winds, and play a role in gene regulation. Although increasing evidence has demonstrated that tumor progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and spread has been unclear.

In the current study, investigators at the Mount Sinai School of Medicine (New York, NY, USA) focused their attention on the histone variant macroH2A (mH2A). They reported in the December 23, 2010, issue of the journal Nature that macroH2A suppressed tumor progression of malignant melanoma.

Working with melanoma cells growing in culture and with a mouse model, they showed that knockdown of mH2A isoforms in melanoma cells of low malignancy resulted in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms reversed this trend in both cell cultures and the animal model.

The investigators found that at the molecular level the tumor-promoting function of mH2A loss was mediated, at least in part, through direct transcriptional increase of the enzyme CDK8 (cyclin-dependent kinase 8), a known oncogene for colorectal cancer.

"We wanted to determine whether macroH2A is a passenger in this process or if it is crucial in the progression of melanoma,” said senior author Dr. Emily Bernstein, assistant professor of oncological sciences and dermatology at Mount Sinai School of Medicine. "CDK8 is highly expressed in aggressive melanoma, suggesting it also plays a major role in the process.”

"Very little is known about melanoma epigenetics or the histone-mediated epigenetic changes in cancer in general, so these findings are a major step forward in our research. As we move ahead, we would like to determine how to inhibit CDK8 function, thereby inhibiting the growth of melanoma, as well as identify additional epigenetic changes in melanoma progression,” said Dr. Bernstein. "What these discoveries really highlight is the need for further studies into the epigenetic code of cancer.”

Related Links:
Mount Sinai School of Medicine