title: Transcription factor LSF-DNMT1 complex dissociation by FQI1 leads to aberrant DNA methylation and gene expression.
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.
authors.affiliation: New England Biolabs, Inc. Ipswich, MA 01938, USA.|MCBB Graduate Program, Boston University, Boston, MA 02215, USA.
authors.forename: Hang Gyeong
authors.initials: HG
authors.lastname: Chin
authors.affiliation: New England Biolabs, Inc. Ipswich, MA 01938, USA.
authors.forename: V K Chaithanya
authors.initials: VK
authors.lastname: Ponnaluri
authors.affiliation: New England Biolabs, Inc. Ipswich, MA 01938, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: New England Biolabs, Inc. Ipswich, MA 01938, USA.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Estève
authors.affiliation: Deptartment of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA 02215, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Schaus
authors.affiliation: MCBB Graduate Program, Boston University, Boston, MA 02215, USA.|Department of Biology, Boston University, Boston, MA 02215, USA.
authors.forename: Ulla
authors.initials: U
authors.lastname: Hansen
authors.affiliation: New England Biolabs, Inc. Ipswich, MA 01938, USA.
authors.forename: Sriharsa
authors.initials: S
authors.lastname: Pradhan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D015363:Quinolones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
chemical_list: C585328:8-(2-ethoxyphenyl)-7,8-dihydro-(1,3)dioxolo(4,5-g)quinolin-6(5H)-one; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015363:Quinolones; C501906:TFCP2 protein, human; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA methylation; HCC; gene expression; transcription factor LSF