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Abstract
The transcription factor LSF is highly expressed in hepatocellular carcinoma (HCC) and promotes oncogenesis. Factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity and exerts anti-proliferative activity. Here, we show that LSF binds directly to the maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1) and its accessory protein UHRF1 both in vivo and in vitro. Binding of LSF to DNMT1 stimulated DNMT1 activity and FQI1 negated the methyltransferase activation. Addition of FQI1 to the cell culture disrupted LSF bound DNMT1 and UHRF1 complexes, resulting in global aberrant CpG methylation. Differentially methylated regions (DMR) containing at least 3 CpGs, were significantly altered by FQI1 compared to control cells. The DMRs were mostly concentrated in CpG islands, proximal to transcription start sites, and in introns and known genes. These DMRs represented both hypo and hypermethylation, correlating with altered gene expression. FQI1 treatment elicits a cascade of effects promoting altered cell cycle progression. These findings demonstrate a novel mechanism of FQI1 mediated alteration of the epigenome by DNMT1-LSF complex disruption, leading to aberrant DNA methylation and gene expression.
Highlights
DNA methylation is one of the major mechanisms for the regulation of genetic information and gene expression in vertebrates [1]
Factor quinolinone inhibitor 1 (FQI1) treatment elicits a cascade of effects promoting altered cell cycle progression. These findings demonstrate a novel mechanism of FQI1 mediated alteration of the epigenome by DNA (cytosine-5) methyltransferase 1 (DNMT1)-LSF complex disruption, leading to aberrant DNA methylation and gene expression
Since p53 recruits DNMT1 and promotes DNA methylation in a p53 dependent manner [25], we investigated if such a relationship exists between DNMT1 and LSF
Summary
DNA methylation is one of the major mechanisms for the regulation of genetic information and gene expression in vertebrates [1]. It maintains gene silencing in the nuclear genome including the repetitive DNA elements [2, 3]. In this mechanism, a methyl group is covalently added at the 5th position of carbon on the cytosine ring in CG, CHG and CHH sequence contexts [4,5,6,7]. Loss of global DNA methylation on the repetitive DNA elements and subsequent alteration in chromatin structure was the first epigenetic change demonstrated in human cancers [8, 9]. Aberrant DNA methylation was demonstrated to be the dominant mechanism in MDS progression to AML correlating with poor clinical outcomes [13], highlighting its relevance to oncogenesis
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