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

doi:10.1016/j.isci.2020.101795

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 journal › Article › peer-review

14 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 language	English
Article number	101795
Journal	iScience
Volume	23
Issue number	12
DOIs	https://doi.org/10.1016/j.isci.2020.101795
State	Published - Dec 18 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Funding

We are grateful to Professor Randall Moon for the Super 8× TOPFlash and 8× FOPFlash plasmids and Professor Tianyan Gao for mouse colon cancer organoids. 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 ). We are grateful to Professor Randall Moon for the Super 8× TOPFlash and 8× FOPFlash plasmids and Professor Tianyan Gao for mouse colon cancer organoids. 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). Conceptualization, C.L. and D.S.W.; Methodology, W.Z. V.M.S. Y.X. T.Y. and M.G.H.; Data Analysis, W.Z. V.M.S. J.S.B. and C.-G.Z.; Supervision, C.L. D.S.W. J.S.B. and C.-G.Z.; Writing, C.L. and D.S.W. C.L. and D.S.W. have partial ownership in a for-profit venture, Epionc, Inc. that seeks to develop small-molecule inhibitors for cancer treatment. In accord with University of Kentucky policies, C.L. and D.S.W. have disclosed this work to the University of Kentucky's Intellectual Property Committee and to a Conflict of Interest Oversight Committee in accord with University of Kentucky policies.

Funders	Funder number
Center for Pharmaceutical Research and Innovation in the College of Pharmacy
University of Kentucky policies
National Institutes of Health (NIH)	R01 CA172379, UL1 TR000117
U.S. Department of Defense	W81XWH-16-1-0635, P30 RR020171, PC150326P2
American Cancer Society	R37 CA227656, T32 CA165990
National Institute of General Medical Sciences	IRG 16-182-28
University of Kentucky
University of Kentucky Markey Cancer Center	P30 CA177558

Keywords

Biochemical Mechanism
Biochemistry
Biological Sciences

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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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.",

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volume = "23",

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AU - Yu, Tianxin

AU - Haney, Meghan G.

AU - Blackburn, Jessica S.

AU - Adeniran, Charles A.

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AB - 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.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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