Regulation of Wnt Signaling Target Gene Expression
by the Histone Methyltransferase DOT1L
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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