Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition.
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.
Lakshmikuttyamma
A
A
Cancer Stem Cell Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 4H4.
Scott
S A
SA
DeCoteau
J F
JF
Geyer
C R
CR
D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
C493966:CDKN2B protein, human; D015820:Cadherins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004791:Enzyme Inhibitors; D012097:Repressor Proteins; D000077209:Decitabine; C407843:SUV39H1 protein, human; D015254:DNA Modification Methylases; D008780:Methyltransferases; D001374:Azacitidine