Abstract 1385: New insights into the roles of histone lysine-specific demethylase 2 (LSD2) in breast cancer

Abstract

Abstract Background: Epigenetic modifiers have been emerging as new players in breast cancer development. FAD-dependent histone demethylases have been proved to play important roles in regulating breast tumor initiation and development. While the role of histone lysine-specific demethylase 1 (LSD1) in breast cancer progression has been well characterized, the activity of its homolog, lysine-specific demethylase 2 (LSD2), in breast cancer is still a riddle that needs to be uncovered. Methods: To explore the precise role of LSD2 in breast cancer, we overexpressed LSD2 protein in MDA-MB-231 cells (LSD2-OE). The phenotypic effect of LSD2-OE on MM231 cells was characterized by proliferation assay, soft agar assay (3D growth), trans-well cell migration and invasion assay and mammosphere formation assay. To extend stem cell-like features study of LSD2 overexpressed MM231 cells, we examined CD44+/CD24- subpopulation by flow cytometry and the expression of several stem cell markers by qPCR and western blot. In addition, we also investigated the potential altered phenotypes of LSD2 knockdown in MM231 cells via RNAi. Results: Results from Oncomine database show that LSD2 expression level is greatly increased in invasive ductal carcinoma (IDC) vs. non-invasive breast cancers. The cellular proliferation assay revealed that LSD2-OE promoted MM231 cell growth. Similarly, LSD2 overexpressed MM231 cells were capable of forming large colonies in soft agar. Trans-well cell migration and invasion assay results indicated LSD2-OE significantly decreased both migration and invasion in MM231 cells. Mammosphere formation assay results showed LSD2 overexpression increased the number of primary and tertiary mammospheres in MM231 cells. Consistent with increase of mammosphere forming efficiency, NANOG and SOX2 were increased by LSD2 overexpression at the protein level. However, LSD2-OE significantly decreased CD44+/CD24- subpopulation. Moreover, siRNA mediated LSD2 depletion significantly decreased cell growth in multiple breast cancer cell lines without altering migration and invasion in MM231 cells. Finally, no obvious phenotypic changes were observed in MM231 cells expressing stable LSD2 shRNA. Conclusion: The multifaceted effects of LSD2 on breast cancer phenotypes may reflect the profound influence of LSD2 activity on chromatin structure and gene expression in the breast cancer genome. Our studies suggest that overexpression of LSD2 facilitates growth and confers stem cell-like traits to breast cancer cells, and transient LSD2 inhibition by siRNA hinders breast cancer cell growth. These results suggest that LSD2 might be a valuable therapeutic target in breast cancer. Citation Format: Lin Chen, Shauna N. Vasilatos, Ye Qin, Steffi Oesterreich, Nancy E. Davidson, Yi Huang. New insights into the roles of histone lysine-specific demethylase 2 (LSD2) in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1385. doi:10.1158/1538-7445.AM2017-1385