Gene first linked to rare disease may trigger skin cancer, other tumors

A gene first identified in connection with a rare disease in which patients develop multiple, benign skin tumors may be a more general player in cancers found throughout the body, according to a report in the May 19, 2006 Cell.

The disease familial cylindromatosis results from the loss of a gene called CYLD, causing tumors known as cylindromas to develop in hair-follicle cells. Earlier studies indicated a role for CYLD in inflammation, but the mechanism behind the gene's control over tumor growth had remained uncertain.

A team led by Reinhard Fässler of the Max Planck Institute of Biochemistry in Germany and his colleagues has now found that CYLD has a second role that explains its ability to keep tumors at bay.

The enzyme chemically modifies the cancer-promoting protein Bcl-3, first identified in connection with some forms of leukemia. That modification bars the oncogenic protein's entry into the cell nucleus, the central command center and storehouse for DNA, where it would otherwise drive the uncontrolled increase in cell numbers characteristic of tumor growth.

The researchers first showed that mice lacking CYLD were highly sensitive to developing skin tumors. Mutant mice exposed to particular chemicals all developed skin tumors compared to half of normal mice experiencing the same exposures. Moreover, the CYLD-deficient mice developed 7-fold more and significantly larger tumors than their control littermates.

Further examination of tumors taken from the mutant mice suggested that the defect stemmed from an increase in cell proliferation rather than cell survival. Isolated CYLD-deficient skin cells, when treated with the tumor-inducing chemicals, began to proliferate due to an accumulation of Bcl-3 in the nucleus, they found. Treatment with a single dose of ultraviolet light--thought to be a trigger of cylindromas--sparked the same reaction in the mutant cells, they found.

"In the absence of CYLD, it is the accumulation of Bcl-3 that is the problem," Fässler said. "Bcl-3 is normally under tight regulation; it is primarily found out in the cytoplasm, with very little in the nucleus." Cytoplasm is the clear, jelly-like material in which all the cell's components are suspended.

"In animals deficient for CYLD, much too much Bcl-3 makes it into the nucleus where it activates genes leading to the growth of tumors."

In normal skin cells, chemical treatment or UV light prompts the transport of CYLD out into the cytoplasm, they reported. Once there, the protein binds and modifies the cancer promoter Bcl-3 to prevent its nuclear accumulation.

In addition to elucidating the cause of cylindromas, the findings might have important implications for understanding the events underlying skin cancer, and perhaps also tumors in other body tissues, the researchers said.

Indeed, the group noticed an intriguing trend--most of the tumors found in the mutant mice developed from cells of the epidermis rather than the hair-follicle cells thought to be involved in cylindromatosis. They therefore conducted a preliminary analysis of CYLD levels in human skin cancers originating from the epidermis, including basal cell carcinomas (BCC) and squamous cell carcinomas (SCC).

BCC and SCC represent the two most common forms of skin cancer, which together affect an estimated one million Americans each year.

"Interestingly, we observed reduced or absent expression of CYLD in more than ten samples of BCC and SCC, respectively," the researchers wrote. "This strongly suggests that CYLD plays a general role as a tumor suppressor, which is in agreement with its ubiquitous expression pattern and with a recent observation showing that CYLD levels are downregulated in several other tumors such as kidney, liver, and uterine cervix."

The researchers are now further examining their CYLD-deficient mice to find out whether the animals also show an increased prevalence of colon tumors. Early indications suggest that they do, according to Fässler.

"We think the CYLD tumor suppressor involved in cylindromas is likely to be important to many, many other tumors," he said.

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The researchers include Ramin Massoumi, Katarzyna Chmielarska, and Reinhard Fassler of the Max Planck Institute of Biochemistry in Martinsried, Germany; Katharina Hennecke and Alexander Pfeifer of Ludwig-Maximilians-Universitat Munchen in Munich, Germany.

This work was supported by the Max Planck Society, Fonds der Chemischen Industrie, and the DFG to R.F.

Massoumi et al.: "Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-kB Signaling." Publishing in Cell 125, 665–677, May 19, 2006. DOI 10.1016/j.cell.2006.03.041 www.cell.com


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