A protein that is largely absent in one type of skin cancer protects an important gene in a cell's defense against harmful mutations from being silenced, researchers at The University of Texas M. D. Anderson Cancer Center report in the July 20 edition of Molecular Cell .
The protein IKKa, expressed at reduced levels in aggressive squamous cell carcinomas both in mice and humans, prevents a vital "checkpoint" gene from being chemically shut down, says Yinling Hu, Ph.D., senior author of the paper and assistant professor in M. D. Anderson's Department of Carcinogenesis at the Science Park - Research Division in Smithville, Texas.
Expression of the checkpoint gene, called 14-3-3o, normally is triggered by the cancer-preventing gene p53 in response to DNA damage in the cell, Hu says. The protein expressed by the checkpoint gene helps to block a defective cell from dividing, allowing its genetic errors to be repaired rather than repeated in a new cell. Cells with damaged genes or genes that are behaving abnormally are the drivers of cancer.
"What we've identified is a mechanism that promotes genetic instability in keratinocytes, a critical type of skin cell that makes up 90 percent of epidermal cells, during the development of human skin cancers," Hu says. They found that the absence or weak expression of IKKa leaves the checkpoint gene vulnerable to silencing.
In a series of experiments reported in the Molecular Cell paper, Hu and colleagues show how IKKa prevents silencing of the checkpoint gene by a chemical process known as methylation. Methyl groups, consisting of a carbon atom surrounded by three hydrogen atoms, attach to specific locations on a gene and prevent it from expressing its protein without altering the gene. The team restored the checkpoint gene's activity by first restoring the expression of IKKa in deficient cells by infecting the cells with a virus designed to express IKKa.