Scientists at Wilmot Cancer Institute have discovered a genomic tug of war in animal studies that may have a significant impact on how patients with myelodysplastic syndromes, such as acute myeloid leukemia, respond to chemotherapy. The study, published in the journal Development, highlights the role of a gene activator called H2A.Z in the effectiveness of chemotherapy drug decitabine.
Decitabine is known to inhibit cancer growth in certain patients, but others show resistance to the drug or develop resistance over time. The researchers found that decitabine triggers a competition between different regions of DNA for H2A.Z. In cases where there is a deficiency of this gene activator, gene expression is halted, leading to cell death. However, many types of cancer have high levels of H2A.Z, which seems to facilitate their ability to overcome the effects of decitabine and continue growing.
The study builds upon previous research that identified distinct subtypes of breast cancer based on the levels of H2A.Z present in tumors. This finding suggests that it may be possible to classify patients based on the amount of H2A.Z in their tumors and determine the effectiveness of decitabine or similar therapies. These personalized medicine diagnostics could be used to guide treatment decisions in the future.
H2A.Z is a type of histone, a group of proteins around which DNA is wrapped. Different histones affect the tightness of DNA spooling, with tighter wrapping protecting the DNA and looser wrapping allowing for the expression of genes. H2A.Z binds DNA loosely, enabling the activation of nearby genes. While it was previously believed to only bind to coding regions of DNA, the study demonstrated that H2A.Z also binds to non-coding DNA sequences in zebrafish.
Previous studies had suggested a connection between H2A.Z and decitabine, and recent research has shown that decitabine can activate non-coding DNA sequences. However, the exact mechanism of this activation was unknown. The team, funded by a pilot award from URMC’s Environmental Health Science Center, used zebrafish embryos to test the connection between decitabine and H2A.Z. The treatment with decitabine caused H2A.Z to migrate towards non-coding regions of DNA, reactivating them, while avoiding coding DNA. This led to reduced gene expression, cell death, and inhibited embryo growth. However, embryos that expressed high levels of H2A.Z, mimicking some cancers, maintained normal gene expression and development.
The researchers also observed the same effect with a toxic chemical called TDCIPP, commonly found in flame retardants and pesticides. TDCIPP caused H2A.Z to shift from coding to non-coding regions of DNA, disrupting gene expression and embryo development. However, embryos that overexpressed H2A.Z were able to counteract the negative effects of the toxin.
The findings suggest that both decitabine and TDCIPP manipulate essential cellular processes to induce cell death. This study has revealed vulnerabilities in cancer cells that could be targeted to improve future cancer therapies.
Although further research is required to confirm these mechanisms in humans and understand how non-coding DNA sequences interact with H2A.Z, the researchers plan to investigate this mechanism in mouse embryonic stem cells as a next step towards understanding its broader implications in mammals.
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