The protein IKK-alpha, expressed at reduced levels in aggressive squamous cell carcinomas, prevents a vital checkpoint gene, 14-3-3-sigma, from being chemically shut down, report researchers from The University of Texas M. D. Anderson Cancer Center.
Expression of 14-3-3-sigma is normally triggered by the cancer-preventing gene p53 in response to DNA damage in the cell. The protein expressed by 14-3-3-sigma helps to block a defective cell from dividing, allowing its genetic errors to be repaired rather than repeated in a new cell.
In a series of experiments, the scientists showed how IKK-alpha prevents silencing of 14-3-3-sigma by methylation. The team also restored 14-3-3-sigma's activity by first restoring the expression of IKK-alpha in deficient cells by infecting the cells with a virus designed to express IKK-alpha.
"DNA methylation is largely responsible for shutting down the checkpoint gene expression in human cancer cells," says Yinling Hu, Ph.D., senior author of the paper and assistant professor in M.D. Anderson's department of carcinogenesis. "Although IKK-alpha can protect the checkpoint gene 14-3-3-sigma from silencing, IKK-alpha itself is frequently impaired in cancer cells. So, we are going to define specific downstream targets of IKK-alpha involved in regulating DNA methylation of the checkpoint gene."
The study will be published in the July 20 edition of Molecular Cell.