Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition

Abstract

Reexpression of hypermethylated tumor suppressor genes using DNA methyltransferase (DNMT) and histone deacetylase inhibitors occurs by a mechanism whereby promoter demethylation is the dominant event. In support of this model, we found in acute myeloid leukemia cells with hypermethylated p15INK4B and E-cadherin promoters that the DNMT inhibitor, 5-aza-2'-deoxycytidine, induced p15INK4B and E-cadherin expression, and decreased levels of DNA methylation, histone H3 lysine 9 (H3K9) methylation and SUV39H1 associated with p15INK4B and E-cadherin promoters. On the basis of these observations, we examined whether promoter demethylation was dominant to H3K9 demethylation in p15INK4B and E-cadherin reexpression. We observed that SUV39H1 short hairpin RNA and chaetocin, a SUV39H1 inhibitor, induced p15INK4B and E-cadherin expression and H3K9 demethylation without promoter demethylation. Reexpression of hypermethylated p15INK4B and E-cadherin required histone H3K9 demethylation that was achieved directly by inhibiting SUV39H1 expression or activity, or indirectly by decreasing the amount of SUV39H1 associated with the p15INK4B and E-cadherin promoters using 5-aza-2'-deoxycytidine. The results from this study highlight the potential of H3K9 methyltransferases as therapeutic targets for reactivating expression of hypermethylated genes.