Epigenetic Regulation of Wnt Signaling by Carboxamide-Substituted Benzhydryl Amines that Function as Histone Demethylase Inhibitors
Wen Zhang,
Vitaliy M. Sviripa,
Yanqi Xie,
Tianxin Yu,
Meghan G. Haney,
Jessica S. Blackburn,
Charles A. Adeniran,
Chang-Guo Zhan,
David S. Watt,
Chunming Liu
Affiliations
Wen Zhang
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA
Vitaliy M. Sviripa
Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA
Yanqi Xie
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA
Tianxin Yu
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA
Meghan G. Haney
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA
Jessica S. Blackburn
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA
Charles A. Adeniran
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Molecular Modeling and Pharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA
Chang-Guo Zhan
Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Molecular Modeling and Pharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA
David S. Watt
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Corresponding author
Chunming Liu
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA; Corresponding author
Summary: Aberrant activation of Wnt signaling triggered by mutations in either Adenomatous Polyposis Coli (APC) or CTNNB1 (β-catenin) is a hallmark of colorectal cancers (CRC). As part of a program to develop epigenetic regulators for cancer therapy, we developed carboxamide-substituted benzhydryl amines (CBAs) bearing either aryl or heteroaryl groups that selectively targeted histone lysine demethylases (KDMs) and functioned as inhibitors of the Wnt pathway. A biotinylated variant of N-((5-chloro-8-hydroxyquinolin-7-yl) (4-(diethylamino)phenyl)-methyl)butyramide (CBA-1) identified KDM3A as a binding partner. KDM3A is a Jumonji (JmjC) domain-containing demethylase that is significantly upregulated in CRC. KDM3A regulates the demethylation of histone H3's lysine 9 (H3K9Me2), a repressive marker for transcription. Inhibiting KDM3 increased H3K9Me2 levels, repressed Wnt target genes, and curtailed in vitro CRC cell proliferation. CBA-1 also exhibited in vivo inhibition of Wnt signaling in a zebrafish model without displaying in vivo toxicity.
