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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Pages (from-to)1608-1621
Number of pages14
JournalChemistry and Biology
Volume22
Issue number12
DOIs
StatePublished - 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

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