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Protein protects anti-cancer gene from chemical shutdown

July 20, 2007

IKKa stops epigenetic silencing of cell cycle checkpoint gene

HOUSTON -- 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 IKK-alpha, 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 14-3-3-sigma, 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 IKK-alpha leaves the checkpoint gene vulnerable to silencing.

In a series of experiments reported in the Molecular Cell paper, Hu and colleagues show how IKK-alpha 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 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," Hu says. "Our finding opens a new avenue for identifying new therapeutic targets for battling cancer. 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. Those targets may be used to prevent silencing of the gene in cancer cells and so allow us to eliminate those cells."

In addition to understanding a critical component in skin cancer, the team notes that other researchers have shown that the checkpoint gene 14-3-3-sigma is silenced in a variety of other human epithelial cancers. Epithelial cells make up the outer layers of skin and the inner linings of many organs, including the lungs and the gastrointestinal, reproductive and urinary tracts.

The checkpoint gene had been known to be silenced by methylation, but the mechanism had not been understood. DNA methylation is known as an epigenetic process, because it affects a gene's activity without changing or damaging the gene itself.

Hu's research group has focused on IKK-alpha, which is an important component of a molecular complex that regulates the development of the lymph and immune systems. Hu and colleagues earlier showed that IKK-alpha is essential for embryonic skin development.

University of Texas M. D. Anderson Cancer Center