Using a protein purification approach, Zhou and his colleagues found that Snail interacts and teams up with its "partner in crime," an enzyme called LSD1, inside the cell. LSD1 is known to change the structure of DNA and shut down the expression of many genes.
LSD1, which stands for lysine-specific demethylase-1 (and is chemically unrelated to the hallucinogen LSD), regulates the structure of the chromosome by removing a key methylation at histone H3, a core component that warps the DNA into compact conformation. This event triggers the "closure" of DNA structure and shuts down gene expression, such as E-cadherin. Zhou's team showed that the N-terminal portion of Snail molecular functions as a "molecular hook" for recruiting LSD1 to the E-cadherin gene, which, in turn, shuts down the expression of E-cadherin and induces tumor cell invasion and metastasis.
"This finding has significant clinical ramification, because chemical compounds or agents that can disrupt the interaction of Snail with LSD1 will have a great therapeutic potential of treating metastatic breast cancer," Zhou said. "Scientists at the Markey Cancer Center are currently exploring this idea and are keen to develop drugs that can treat metastatic cancer."
Breast cancer is the most common cancer in women. Approximately 90 percent of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells, and the average survival after documentation of metastasis is approximately two years.
"An understanding of the mechanism underlying the biology of breast cancer metastasis will provide novel therapeutic approaches to combat this life-threatening disease," Zhou said.
|Contact: Keith Hautala|
University of Kentucky