Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Zibo Zhao; Lu Wang; Taryn James; Youngeun Jung; Ikyon Kim; Renxiang Tan; F. Michael Hoffmann; Wei Xu

doi:10.1016/j.chembiol.2015.10.011

Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Zibo Zhao, Lu Wang, Taryn James, Youngeun Jung, Ikyon Kim, Renxiang Tan, F. Michael Hoffmann, Wei Xu^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

35 Scopus citations

Abstract

ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.

Original language	English (US)
Pages (from-to)	1608-1621
Number of pages	14
Journal	Chemistry and Biology
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2015.10.011
State	Published - Dec 17 2015

Funding

We thank Dr. Kenneth Satyshur for the molecular docking of CHIP E3 ligase and Dip G, and Dr. Weibo Luo and Gregg L. Semenza for providing the CHIP ΔU-Box and ΔTPR plasmids. We acknowledge Dr. Richard R. Burgess for critical review of the manuscript. T.J. was supported by T32ES007015 and PHRMA 2012080067. This project is supported by DOD ERA of HOPE Scholar Award ( W81XWYH-11-1-0237 ) to W.X. and also by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) grant UL1TR000427 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Keywords

CHIP E3 ligase
Diptoindonesin G
breast cancer
estrogen receptor

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

UN SDGs

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

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10.1016/j.chembiol.2015.10.011

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title = "Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G",

abstract = "ERβ is regarded as a {"}tumor suppressor{"} in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.",

keywords = "CHIP E3 ligase, Diptoindonesin G, breast cancer, estrogen receptor",

author = "Zibo Zhao and Lu Wang and Taryn James and Youngeun Jung and Ikyon Kim and Renxiang Tan and Hoffmann, {F. Michael} and Wei Xu",

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doi = "10.1016/j.chembiol.2015.10.011",

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AU - Zhao, Zibo

AU - Wang, Lu

AU - James, Taryn

AU - Jung, Youngeun

AU - Kim, Ikyon

AU - Tan, Renxiang

AU - Hoffmann, F. Michael

AU - Xu, Wei

PY - 2015/12/17

Y1 - 2015/12/17

N2 - ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.

AB - ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.

KW - CHIP E3 ligase

KW - Diptoindonesin G

KW - breast cancer

KW - estrogen receptor

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Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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