Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties

Area of Science:

• Epigenetics
• Cancer Biology
• Chemical Biology

Background:

• Histone modification, specifically H3K4 methylation, regulates gene expression and is linked to active promoters.
• Lysine-specific demethylase 1 (LSD1/KDM1) removes methyl groups from H3K4, suppressing gene expression.
• The role of LSD1 in cancer pathophysiology is largely unknown.

Purpose of the Study:

• To develop specific small molecule inhibitors of LSD1.
• To investigate the effects of LSD1 inhibition on gene expression and cancer cell proliferation.
• To identify cancer types selectively sensitive to LSD1 inhibition.

Main Methods:

• Development of bioactive small molecule inhibitors of LSD1.
• In vivo assessment of H3K4 methylation enhancement and gene derepression.
• Proliferation assays on various cancer cell lines (pluripotent and non-pluripotent) and normal somatic cells.
• RNA interference-mediated knockdown of LSD1.
• Analysis of LSD1 protein levels in cancer cells and tissues.

Main Results:

• LSD1 inhibitors enhanced H3K4 methylation and derepressed epigenetically silenced genes in vivo.
• The compounds potently inhibited proliferation of pluripotent cancer cells (teratocarcinoma, embryonic carcinoma, seminoma) and embryonic stem cells expressing Oct4 and Sox2.
• Minimal growth inhibition was observed in non-pluripotent cancer cells and normal somatic cells.
• LSD1 knockdown phenocopied the selective growth inhibition.
• Elevated LSD1 protein levels were found in pluripotent cancer cells and human testicular seminoma tissues.

Conclusions:

• LSD1 inhibitors are effective in selectively targeting and inhibiting pluripotent cancer cell proliferation.
• LSD1 and H3K4 methylation represent crucial cancer-selective epigenetic targets in cancers with pluripotent stem cell properties.
• These findings establish LSD1 as a promising therapeutic target for specific cancer types.