H2A.Z.2: a chromatin regulator that plays a role in Malignant Melanoma
Lay summary by Anne Mirabella
DNA in human cells is organised by being wrapped around core proteins called histones forming complexes named nucleosomes. All together this structure is known as chromatin. DNA organization is quite flexible as it can be tightly compacted in inactive regions or can be found in open and accessible states in regions of the genome where genes are transcribed. The transition between active and inactive regions is regulated mostly by histones through a variety of mechanisms. Histones come in four common types but there are notable exceptions, known as histone variants. Vardabasso et al., have investigated the role of the poorly characterized histone variant H2A.Z.2 in the context of cancer.
An international collaboration between two groups led by Emily Bernstein and Sandra Hake has identified a chromatin regulator that plays a role in malignant skin cancer cells (melanoma) and potentially a new target for sensitising melanoma cancer cells to targeted drugs. Chiara Vardabasso and colleagues found that there is a high quantity of H2A.Z.2 in melanoma cells and upon H2A.Z.2 depletion, cells cease proliferating. Furthermore, with genome wide analysis the group uncovered part of the molecular mechanism underlying this process. H2A.Z.2 regulates genes that are responsible for cell cycle progression and are targeted by E2F, a protein known to bind accessible DNA and switch genes on at crucial points when the cells are preparing to replicate.
A protein called BRD2 previously reported to play a role in cancer formation is found to interact with H2A.Z.2 containing nucleosomes and also to be highly present in melanoma cells. Expression of BRD2 in melanoma cells is shown to be dependent on and regulated by H2A.Z.2. Once H2A.Z.2 is depleted in melanoma cells, BRD2 levels also decrease.
The authors have found that high levels of H2A.Z.2 correlate with poor survival of metastatic melanoma patients. Currently there are no drugs that specifically target histones; however, there are inhibitors designed to target the BRD protein family (BET inhibitors). Combination of BET inhibitors with H2A.Z.2 depletion causes melanoma cell death. These findings could be of translational impact in the clinic. Metastatic melanoma acquires resistance to the majority of targeted therapies; and thus combinatorial therapy with BET inhibitors and inhibitors of histone regulators represents an interesting avenue of further investigation.
For further information
Read the Molecular Cell original research article which this summary is based on Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma (June 2015).
Visit the profile of the research ambassador, Anne Mirabella, who wrote this summary.
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