Abstract
An aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance the tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1-mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4-overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a “primed” enhancer state that is susceptible to reactivation, leading to aberrant PpG expression.
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•Pluripotency genes are partially repressed in F9 ECCs post-differentiation•Oct4 interacts with Lsd1 and inhibits its histone demethylation activity•Inhibition of Lsd1 by Oct4 leads to retention of H3K4me1 at pluripotency gene enhancers•Retention of H3K4me1 inhibits DNA methylation leading to the “primed” enhancer state
AlAbdi et al. show that aberrant expression of Oct4 in cancer stem cells can facilitate the establishment of the “primed” enhancer state of pluripotency genes. Reactivation of these enhancers would support tumorigenicity.