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.
authors.affiliation: McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Taryn
authors.initials: T
authors.lastname: James
authors.affiliation: College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Republic of Korea.
authors.forename: Youngeun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Republic of Korea.
authors.forename: Ikyon
authors.initials: I
authors.lastname: Kim
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210093, PR China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: F Michael
authors.initials: FM
authors.lastname: Hoffmann
authors.affiliation: McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA. Electronic address: wxu@oncology.wisc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D055550:Protein Stability / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D054852:Small Molecule Libraries; C543798:diptoindonesin G
keywords: CHIP E3 ligase; Diptoindonesin G; breast cancer; estrogen receptor