Epigenetic Regulation of Wnt Signaling by Carboxamide-Substituted Benzhydryl Amines that Function as Histone Demethylase Inhibitors

Authors

Wen Zhang, University of KentuckyFollow
Vitaliy M. Sviripa, University of KentuckyFollow
Yanqi Xie, University of KentuckyFollow
Tianxin Yu, University of KentuckyFollow
Meghan G. Haney, University of KentuckyFollow
Jessica S. Blackburn, University of KentuckyFollow
Charles A. Adeniran, University of KentuckyFollow
Chang-Guo Zhan, University of KentuckyFollow
David S. Watt, University of KentuckyFollow
Chunming Liu, University of KentuckyFollow

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.

Document Type

Article

Publication Date

12-18-2020

Notes/Citation Information

Published in iScience, v. 23, issue 12, 101795.

© 2020 The Author(s)

This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.isci.2020.101795

Funding Information

C.L. and D.S.W. were supported by NIH R01 CA172379 from the National Institutes of Health and by NIH UL1 TR000117 from the National Institutes of Health to the University of Kentucky’s Center for Clinical and Translational Science. D.S.W. was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense (DoD) Prostate Cancer Research Program Award W81XWH-16-1-0635 [Grant Log# PC150326P2], and NIH P30 RR020171 from the National Institute of General Medical Sciences to L. Hersh. V.M.S. was supported by grant IRG 16-182-28 from the American Cancer Society. J.S.B. and M.G.H. are supported by NIH R37 CA227656 and T32 CA165990, respectively. This study is also supported by Markey Cancer Center (P30 CA177558).

Repository Citation

Zhang, Wen; Sviripa, Vitaliy M.; Xie, Yanqi; Yu, Tianxin; Haney, Meghan G.; Blackburn, Jessica S.; Adeniran, Charles A.; Zhan, Chang-Guo; Watt, David S.; and Liu, Chunming, "Epigenetic Regulation of Wnt Signaling by Carboxamide-Substituted Benzhydryl Amines that Function as Histone Demethylase Inhibitors" (2020). Molecular and Cellular Biochemistry Faculty Publications. 180.
https://uknowledge.uky.edu/biochem_facpub/180