title: Regulation of Wnt signaling target gene expression by the histone methyltransferase DOT1L.
abstract: The histone methyltransferase DOT1L, solely responsible for histone H3 lysine 79 (H3K79) methylation, is associated with gene activation. Human leukemias carrying MLL gene rearrangements aberrantly recruit DOT1L to leukemogenic genes leading to increased H3K79 methylation and their transcriptional activation. Recent studies suggest that Wnt-targeted genes also depend on H3K79 methylation. Employing a chemical biology approach, the requirement for H3K79 methylation was investigated in Wnt pathway-inducible HEK293 cells and human colon adenocarcinoma-derived cell lines by inhibiting DOT1L with EPZ004777, a selective and potent S-adenosylmethionine competitive inhibitor. Our findings indicate that H3K79 methylation is not essential for the canonical Wnt signaling pathway, in particular for maintenance or activation of Wnt pathway target gene expression. Furthermore, H3K79 methylation is not elevated in human colon carcinoma samples in comparison with normal colon tissue. Therefore, our findings indicate that inhibition of DOT1L histone methyltransferase activity is likely not a viable therapeutic strategy in colon cancer.
authors.affiliation: Department of Pathology, ‡Departments of Internal Medicine and Human Genetics, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Garrett S
authors.initials: GS
authors.lastname: Gibbons
authors.forename: Scott R
authors.initials: SR
authors.lastname: Owens
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C581325:EPZ004777; D004791:Enzyme Inhibitors; D006657:Histones; D010671:Phenylurea Compounds; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine; D000241:Adenosine