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

Producción científica: Article › revisión exhaustiva

26 Citas (Scopus)

Resumen

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.

Idioma original	English
Número de artículo	101795
Publicación	iScience
Volumen	23
N.º	12
DOI	https://doi.org/10.1016/j.isci.2020.101795
Estado	Published - dic 18 2020

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Publisher Copyright:
© 2020 The Author(s)

Financiación

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.

Financiadores	Número del financiador
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

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

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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AU - Haney, Meghan G.

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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

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Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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