DACT3 Is an Epigenetic Regulator of Wnt/β-Catenin Signaling in Colorectal Cancer and Is a Therapeutic Target of Histone Modifications

Xia Jiang; Jing Tan; Jingsong Li; Saul Kivimäe; Xiaojing Yang; Li Zhuang; Puay Leng Lee; Mark T.W. Chan; Lawrence W. Stanton; Edison T. Liu; Benjamin N.R. Cheyette; Qiang Yu

doi:10.1016/j.ccr.2008.04.019

DACT3 Is an Epigenetic Regulator of Wnt/β-Catenin Signaling in Colorectal Cancer and Is a Therapeutic Target of Histone Modifications

Xia Jiang, Jing Tan, Jingsong Li, Saul Kivimäe, Xiaojing Yang, Li Zhuang, Puay Leng Lee, Mark T.W. Chan, Lawrence W. Stanton, Edison T. Liu, Benjamin N.R. Cheyette, Qiang Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

220 Citations (Scopus)

Abstract

Genetic and epigenetic defects in Wnt/β-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/β-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly derepressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/β-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/β-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/β-catenin signaling in colorectal cancer.

Original language	English
Pages (from-to)	529-541
Number of pages	13
Journal	Cancer Cell
Volume	13
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2008.04.019
Publication status	Published - 10 Jun 2008
Externally published	Yes

Keywords

CELLCYCLE
DNA

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10.1016/j.ccr.2008.04.019

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title = "DACT3 Is an Epigenetic Regulator of Wnt/β-Catenin Signaling in Colorectal Cancer and Is a Therapeutic Target of Histone Modifications",

abstract = "Genetic and epigenetic defects in Wnt/β-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/β-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly derepressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/β-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/β-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/β-catenin signaling in colorectal cancer.",

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author = "Xia Jiang and Jing Tan and Jingsong Li and Saul Kivim{\"a}e and Xiaojing Yang and Li Zhuang and Lee, {Puay Leng} and Chan, {Mark T.W.} and Stanton, {Lawrence W.} and Liu, {Edison T.} and Cheyette, {Benjamin N.R.} and Qiang Yu",

year = "2008",

month = jun,

day = "10",

doi = "10.1016/j.ccr.2008.04.019",

language = "English",

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journal = "Cancer Cell",

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T1 - DACT3 Is an Epigenetic Regulator of Wnt/β-Catenin Signaling in Colorectal Cancer and Is a Therapeutic Target of Histone Modifications

AU - Jiang, Xia

AU - Tan, Jing

AU - Li, Jingsong

AU - Kivimäe, Saul

AU - Yang, Xiaojing

AU - Zhuang, Li

AU - Lee, Puay Leng

AU - Chan, Mark T.W.

AU - Stanton, Lawrence W.

AU - Liu, Edison T.

AU - Cheyette, Benjamin N.R.

AU - Yu, Qiang

PY - 2008/6/10

Y1 - 2008/6/10

N2 - Genetic and epigenetic defects in Wnt/β-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/β-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly derepressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/β-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/β-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/β-catenin signaling in colorectal cancer.

AB - Genetic and epigenetic defects in Wnt/β-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/β-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly derepressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/β-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/β-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/β-catenin signaling in colorectal cancer.

KW - CELLCYCLE

KW - DNA

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DO - 10.1016/j.ccr.2008.04.019

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SN - 1535-6108

VL - 13

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EP - 541

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JF - Cancer Cell

IS - 6

ER -

DACT3 Is an Epigenetic Regulator of Wnt/β-Catenin Signaling in Colorectal Cancer and Is a Therapeutic Target of Histone Modifications

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Keywords

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