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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish
Article number101795
JournaliScience
Volume23
Issue number12
DOIs
StatePublished - Dec 18 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • Biochemical Mechanism
  • Biochemistry
  • Biological Sciences

ASJC Scopus subject areas

  • General

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