GSE168706
Cancer-associated E239K mutation of LSD1 promotes the migration and invasion of luminal breast cancer cells by reducing the expression of ERa
Background: Epithelial to mesenchymal transition (EMT) plays an essential role in the metastasis of breast cancer by regulating the migration and invasion of cancer cells. Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates EMT. However, the functional effects of the mutation on LSD1 in breast cancer remain unclear.  Results: An E239K mutation of LSD1 was identified from TCGA Breast Invasive Carcinoma cohort. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with the wild-type LSD1, but not the E239K mutated LSD1, suppressed the increased invasion of the LSD1 knockdown cells, demonstrating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion of breast cancer cells. Further analysis showed that the E239K mutation of LSD1 led to decreased expression of estrogen receptor a (ERa), which subsequently increased the expression of Slug, a master transcription factor that promoted EMT. Most importantly, the E239K mutation of LSD1 disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of ERa gene. The reduced enrichment of LSD1 at the promoter region of ERa gene caused enhanced histone H3K9 methylation, which in turn suppressed the transcription of ERa gene.  Conclusions: The E239K mutation of LSD1 promotes the migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3, which reduces the expression of ERa by enhancing the histone H3K9 methylation. Overall design: Total RNA obtained from MCF7 cells stably express LSD1 shRNA, or rescued with LSD1 WT,or LSD1 E239K upon LSD1 KD.