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Transcription Factor LSF-DNMT1 Complex Dissociation by FQI1 Leads to Aberrant DNA Methylation and Gene Expression

Transcription Factor LSF-DNMT1 Complex Dissociation by FQI1 Leads to Aberrant DNA Methylation and Gene Expression

Hang Gyeong Chin, V K Chaithanya Ponnaluri, Guoqiang Zhang, Pierre-Olivier Estève, Scott E Schaus, Ulla Hansen, Sriharsa Pradhan

Oncotarget. 2016 Dec 13;7(50):83627-83640.

PMID: 27845898

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP599151356	FQI1		599151-35-6	Price

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