BHC80 is Critical in Suppression of Snail-LSD1 Interaction and Breast Cancer Metastasis

Breast cancer metastasis is a life threatening disease for. many women worldwide. Approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis oftumor cells, and the average time to live after documentation of metastasis is sadly only about 2 years. A cellular event called epithelial-mesenchymal transition (EMT) has been found to be critical in the metastasis process. Snail is a master regulator for EMT induction. It suppresses the expression of E-cadherin, and induces tumor cells to change from "static" to "mobile" in appearance and start to migrate, which are signals for cancers to become metastatic. We recently found that Snail needs to team up with a protein named LSDI (lysine-specific demethylase 1) to suppress E-cadherin and induce EMT. According to our findings, Snail uses its SNAG domain as a molecular hook to recruit LSDI for E-cadherin suppression, and the interplay between Snail and LSD I can be disrupted by another protein named BHC80. Loss ofBHC80 enhances the interaction ofSnail with LSDI and correlates with poor prognosis in women with breast cancer. The objective ofthis proposal is to further explore the role of BHC80 on the regulation ofSnail-LSD I interaction and EMT. Accordingly, we have designed our experiments as follows: 1. We will clarifY exactly how BHC80 disrupts the Snail-LSD I interaction.as well as their suppression on E-cadherin expression. Based on the protein structure of BHC80, we hypothesize that BHC80 uses its PHD finger to interact with the SNAG molecular hook, and this results in the dissociation of LSD I from Snail and subsequent loss of E-cadherin suppression. Furthermore, we suggest that the disruption of the Snail-LSD1 interaction makes the proteins unstable and easy to degrade. We will use different molecule approaches to test our hypotheses. 2. We will investigate this molecular event at the cellular level, and test whether disruption of the SnailLSDI interaction by BHC80 can make breast cancer cells become less metastatic. 3. We will extend our studies to the functional interplay among Snail, LSDI and BHC80 in mouse and human breast cancer, and examine the correlation between the expression of these molecules in breast twnor samples.