title: Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure-activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI(50)s) and for inhibition of LSF transactivation (IC(50)s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.
authors.affiliation: Departments of Biology and Chemistry, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Grant
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bishop
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Christadore
authors.forename: Girish
authors.initials: G
authors.lastname: Barot
authors.forename: Hang Gyeong
authors.initials: HG
authors.lastname: Chin
authors.forename: Sarah
authors.initials: S
authors.lastname: Woodson
authors.forename: John
authors.initials: J
authors.lastname: Kavouris
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sherman
authors.forename: Tracy
authors.initials: T
authors.lastname: Meehan
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Sriharsa
authors.initials: S
authors.lastname: Pradhan
authors.forename: Laura A
authors.initials: LA
authors.lastname: Briggs
authors.forename: William H
authors.initials: WH
authors.lastname: Andrews
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Scott E
authors.initials: SE
authors.lastname: Schaus
authors.forename: Ulla
authors.initials: U
authors.lastname: Hansen
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008956:Models, Chemical; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009857:Oncogenes; D015363:Quinolones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C585328:8-(2-ethoxyphenyl)-7,8-dihydro-(1,3)dioxolo(4,5-g)quinolin-6(5H)-one; D052117:Benzodioxoles; D004268:DNA-Binding Proteins; D015363:Quinolones; C501906:TFCP2 protein, human; D014157:Transcription Factors