Abstract
Epigenetic abnormalities play a vital role in the progression of ovarian cancer. Lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in ovarian tumors. However, the upstream regulator of LSD1 expression in this cancer remains elusive. Here, we show that epidermal growth factor (EGF) signaling upregulates LSD1 protein levels in SKOV3 and HO8910 ovarian cancer cells overexpressing both LSD1 and the EGF receptor. This effect is correlated with a decrease in the dimethylation of H3K4, a major substrate of LSD1, in an LSD1-dependent manner. We also show that inhibition of PI3K/AKT, but not MEK, abolishes the EGF-induced upregulation of LSD1 and cell migration, indicating that the PI3K/PDK1/AKT pathway mediates the EGF-induced expression of LSD1 and cell migration. Significantly, LSD1 knockdown or inhibition of LSD1 activity impairs both intrinsic and EGF-induced cell migration in SKOV3 and HO8910 cells. These results highlight a novel mechanism regulating LSD1 expression and identify LSD1 as a promising therapeutic target for treating metastatic ovarian cancer driven by EGF signaling.
Highlights
Epigenetic abnormalities play a vital role in the progression of ovarian cancer
We show that LSD1 is overexpressed in SKOV3, HO8910, and 3AO ovarian cancer cells, and its levels increase in parallel with increased levels of Epidermal growth factor receptor (EGFR)
We show that epidermal growth factor (EGF) induces upregulation of LSD1, with a concomitant reduction of its substrate H3K4me[2], which mediates the EGF-induced migration of SKOV3 and HO8910 ovarian cancer cells
Summary
Epigenetic abnormalities play a vital role in the progression of ovarian cancer. Lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in ovarian tumors. We show that epidermal growth factor (EGF) signaling upregulates LSD1 protein levels in SKOV3 and HO8910 ovarian cancer cells overexpressing both LSD1 and the EGF receptor This effect is correlated with a decrease in the dimethylation of H3K4, a major substrate of LSD1, in an LSD1-dependent manner. LSD1 knockdown or inhibition of LSD1 activity impairs both intrinsic and EGF-induced cell migration in SKOV3 and HO8910 cells These results highlight a novel mechanism regulating LSD1 expression and identify LSD1 as a promising therapeutic target for treating metastatic ovarian cancer driven by EGF signaling. EGF upregulates LSD1 protein levels via activation of the PI3K/AKT pathway, but not the MAPK/ERK pathway This effect is correlated with an expected decrease in the levels of H3K4me[2], a major substrate of LSD1, in an LSD1-dependent manner. The results provided in this report suggest that targeting LSD1 may be an effective approach for inhibiting the progression of ovarian cancer, EGFR signaling-dependent progression
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