TY - JOUR
T1 - Epigenetic Regulation of Wnt Signaling by Carboxamide-Substituted Benzhydryl Amines that Function as Histone Demethylase Inhibitors
AU - Zhang, Wen
AU - Sviripa, Vitaliy M.
AU - Xie, Yanqi
AU - Yu, Tianxin
AU - Haney, Meghan G.
AU - Blackburn, Jessica S.
AU - Adeniran, Charles A.
AU - Zhan, Chang Guo
AU - Watt, David S.
AU - Liu, Chunming
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/12/18
Y1 - 2020/12/18
N2 - 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.
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.
KW - Biochemical Mechanism
KW - Biochemistry
KW - Biological Sciences
UR - http://www.scopus.com/inward/record.url?scp=85097000523&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097000523&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101795
DO - 10.1016/j.isci.2020.101795
M3 - Article
AN - SCOPUS:85097000523
VL - 23
JO - iScience
JF - iScience
IS - 12
M1 - 101795
ER -