New research by Roswell Park Cancer Institute (RPCI) scientists may help explain how cancer develops. In a study published in the journal Cancer Biology and Therapy*, authors Keshav K. Singh, PhD, and Dominic J. Smiraglia, PhD, of RPCI's Department of Cancer Genetics, analyzed defects in two major cellular mechanisms - dysfunction of mitochondria and abnormal epigenetic changes of the genome - and discovered that these alterations are linked in cancer.
Mitochondria, the power plants that produce energy within each cell, perform multiple functions within cells, including the generation of the basic building blocks of DNA. Mitochondria contain their own DNA (mitochondrial DNA). Changes in mitochondrial DNA copy numbers are associated with development of cancer and poor cancer survival.
Over 1.8 meters of DNA is packed into the nucleus of every cell. Precise packaging of the DNA is essential for this to be possible. Researchers have previously reported that how the genome is packaged is highly dynamic and critical to cellular behavior. This dynamic packaging of the genome is tightly regulated by a set of chemical modifications that occur on the DNA and proteins. The study of these modifications is described as "epigenetics." DNA methylation is one type of epigenetic change which was studied in this research. Methylation changes in the nuclear genome play a key role in human tumorigenesis.
Researchers investigated whether changes in the mitochondrial DNA (mtDNA), which is commonly seen in a number of human tumors, could induce methylation changes in the nucleus. They used the Restriction Landmark Genomic Scanning (RLGS) method to identify genes that acquire changes in DNA methylation in response to the depletion of mtDNA. These studies provide the first direct evidence that mitochondria regulate epigenetic modifications in the nucleus that may contribute to tumorigenesis.
Under the direction of Dr. Singh, researchers eliminated normal mitochondrial function in cell lines, thereby creating what they labeled "rho-zero" cells. The rho-zero cells and normal cells were then both evaluated for the pattern of DNA abnormalities.
The researchers found that mitochondrial impairment induces epigenetic DNA abnormalities in the nuclear genome and that some, but not all, of the changes induced by the depletion of the mitochondrial genome can be reversed by reintroduction of the mitochondria.
This is the first demonstration of how defects in the mitochondria can impact the DNA regulatory epigenetic mechanisms of the cell. These changes can alter the genes expressed in the cell and therefore the behavior of the cell, which in turn can lead to cancer development.
"Our research has shed a novel light on the relationship between the DNA of the cell and the energy source which powers that cell. Further studies may reveal the exact nature of the mitochondrial signal that triggers the epigenetic response and aid in the understanding of the mechanisms associated with tumorigenesis and ultimately impact the treatment of cancer," said Dr. Singh.
Roswell Park Cancer Institute, founded in 1898, is the nation's first cancer research, treatment and education center. The Institute was one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation's leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. roswellpark
* Commentary regarding this study was published by Cancer Biology and Therapy and can be accessed here.
Roswell Park Cancer Institute
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