Abstract:

Lysine-specific demethylase 1 (LSD1) is an important histone demethylase that mediates epithelial to mesenchymal transition (EMT). The E239K mutation of LSD1 was identified in a luminal breast cancer patient from the COSMIC Breast Cancer dataset. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with WT LSD1, but not E239K mutated LSD1, suppressed the invasion and migration of the LSD1 knockdown cells, indicating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion and migration of MCF7 cells. Further analysis showed that the E239K mutation abolished LSD1-mediated invasion and migration of MCF7 cells through downregulation of estrogen receptor α (ERα). Most importantly, the E239K mutation disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of the ERα gene; the reduced enrichment of LSD1 at the promoter region of the ERα gene caused enhanced histone H3K9 methylation, which subsequently suppressed the transcription of the ERα gene. In summary, the E239K mutation abolishes the suppressive function of LSD1 on migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3.