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Researchers at the University of Rochester Medical Center's Wilmot Cancer Institute have made a significant discovery in the fight against certain myelodysplastic syndromes like acute myeloid leukemia. Their study, recently published in the journal Development, investigates the effects of the chemotherapy drug decitabine and its interaction with a gene activator called H2A.Z.
Decitabine's Interaction with DNA
Decitabine, known for its role in stunting cancer growth, operates by engaging different DNA regions in a "genomic tug of war." Patrick Murphy, Ph.D., assistant professor of Biomedical Genetics and Biology at the University of Rochester Medical Center, explained, “Two years ago, we published a paper where we identified different subtypes of breast cancer based on the amount of H2A.Z in tumors. If our findings bear out in humans, we may be able to classify patients based on how much H2A.Z is in their tumor, and then decide whether or not this therapy is going to be more or less effective. So, it could eventually be used alongside personalized medicine diagnostics.”
H2A.Z, a histone protein, plays a critical role in how DNA is spooled and read within a cell. It binds DNA loosely, facilitating the activation of nearby genes. Interestingly, Murphy and postdoctoral associate Fanju Meng, Ph.D., discovered that H2A.Z also binds to non-coding DNA in zebrafish, challenging previous assumptions about its exclusive association with coding DNA.
The Zebrafish Embryo Study
The team tested the relationship between decitabine and H2A.Z using zebrafish embryos. When treated with decitabine, H2A.Z was drawn towards non-coding regions of DNA, reactivating them, while simultaneously moving away from coding DNA. This shift resulted in reduced gene expression, cell death, and hindered embryo growth. However, in embryos with high H2A.Z levels, mimicking some cancer types, the tug of war was balanced, allowing normal gene expression and development.
The study also examined the impact of a common toxic chemical, TDCIPP, used in flame retardants and pesticides. This toxin caused a similar shift in H2A.Z from coding to non-coding DNA regions, disrupting embryo development. But, embryos with an overexpression of H2A.Z were shielded from TDCIPP's harmful effects.
Implications and Future Research
“These external stressors—decitabine and TDCIPP—hijack essential aspects of cellular machinery to cause cell death,” Murphy remarked. The research sheds light on critical vulnerabilities in cancer cells that could be leveraged to enhance future cancer treatments.
The next step involves studying this mechanism in mouse embryonic stem cells, transitioning from zebrafish to mammals. This research holds promise for understanding and potentially overcoming cancer resistance to chemotherapy, particularly in treatments involving decitabine.
Decitabine's Interaction with DNA
Decitabine, known for its role in stunting cancer growth, operates by engaging different DNA regions in a "genomic tug of war." Patrick Murphy, Ph.D., assistant professor of Biomedical Genetics and Biology at the University of Rochester Medical Center, explained, “Two years ago, we published a paper where we identified different subtypes of breast cancer based on the amount of H2A.Z in tumors. If our findings bear out in humans, we may be able to classify patients based on how much H2A.Z is in their tumor, and then decide whether or not this therapy is going to be more or less effective. So, it could eventually be used alongside personalized medicine diagnostics.”
H2A.Z, a histone protein, plays a critical role in how DNA is spooled and read within a cell. It binds DNA loosely, facilitating the activation of nearby genes. Interestingly, Murphy and postdoctoral associate Fanju Meng, Ph.D., discovered that H2A.Z also binds to non-coding DNA in zebrafish, challenging previous assumptions about its exclusive association with coding DNA.
The Zebrafish Embryo Study
The team tested the relationship between decitabine and H2A.Z using zebrafish embryos. When treated with decitabine, H2A.Z was drawn towards non-coding regions of DNA, reactivating them, while simultaneously moving away from coding DNA. This shift resulted in reduced gene expression, cell death, and hindered embryo growth. However, in embryos with high H2A.Z levels, mimicking some cancer types, the tug of war was balanced, allowing normal gene expression and development.
The study also examined the impact of a common toxic chemical, TDCIPP, used in flame retardants and pesticides. This toxin caused a similar shift in H2A.Z from coding to non-coding DNA regions, disrupting embryo development. But, embryos with an overexpression of H2A.Z were shielded from TDCIPP's harmful effects.
Implications and Future Research
“These external stressors—decitabine and TDCIPP—hijack essential aspects of cellular machinery to cause cell death,” Murphy remarked. The research sheds light on critical vulnerabilities in cancer cells that could be leveraged to enhance future cancer treatments.
The next step involves studying this mechanism in mouse embryonic stem cells, transitioning from zebrafish to mammals. This research holds promise for understanding and potentially overcoming cancer resistance to chemotherapy, particularly in treatments involving decitabine.