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Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G
Zibo Zhao1, Lu Wang1, Taryn James1
1McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
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.
Insights
Diptoindonesin G stabilizes Estrogen Receptor beta (ERβ), enhancing its tumor-suppressing activity in breast cancer. This compound also reduces Estrogen Receptor alpha (ERα) levels, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Estrogen Receptor beta (ERβ) exhibits tumor-suppressive properties in breast cancer, but its therapeutic potential is limited by its loss in aggressive forms.
- Estrogen Receptor alpha (ERα) plays a contrasting role, often promoting proliferation in breast cancer.
Purpose of the Study:
- To identify novel small molecules that stabilize ERβ and modulate ERα/ERβ activity.
- To investigate the mechanism of action for identified compounds targeting ERβ in breast cancer.
Main Methods:
- Small-molecule library screening for ERβ stabilizers.
- Assessment of Diptoindonesin G (Dip G) effects on ERα and ERβ protein stability and activity.
- Investigation of Dip G's molecular target using biochemical assays.
Main Results:
- Diptoindonesin G (Dip G) was identified as an ERβ stabilizer, increasing ERβ protein stability and anti-proliferative effects.
- Dip G decreased ERα protein levels and attenuated its proliferative effects.
- Dip G was found to target the CHIP E3 ubiquitin ligase, indirectly modulating both ERα and ERβ.
Conclusions:
- Diptoindonesin G acts as a dual-functional molecule, reciprocally controlling ERα and ERβ stability and activity via CHIP.
- ERβ stabilization by Dip G presents a promising avenue for developing novel ERβ-targeted breast cancer therapies.