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Published on: May 30, 2025
Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and
Lauren Hong1, Natecia L Williams2, Maya Jaffe1
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; and Emory University, Atlanta, Georgia, USA.
Abstract:
Scientists have used pharmacological inhibitors of polycomb proteins to restore the expression of tumor suppressor genes and stop cancer proliferation and invasion. A major limitation of this approach is that key transcriptional activators, such as TP53 and BAF SWI/SNF, are often mutated in cancer. Poor clinical results for polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), could discourage the further development of epigenetic monotherapies. Here, we performed epigenome actuation with a synthetic reader-actuator (SRA) that binds trimethylated histone H3 lysine 27 in polycomb chromatin and modulates core transcriptional activators. In SRA-expressing TNBC BT-549 cells, 122 genes become upregulated ≥2-fold, including the genes involved in cell death, cell cycle arrest, and migration inhibition. The SRA-expressing spheroids showed reduced size in Matrigel and loss of invasion. Therefore, targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and stimulate anti-cancer phenotypes, and further development of robust gene regulators might benefit TNBC patients.
Insights
Scientists developed a synthetic reader-actuator (SRA) to target polycomb chromatin, reactivating tumor suppressor genes. This approach shows promise for treating triple-negative breast cancer (TNBC) by inhibiting cancer proliferation and invasion.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Therapeutics
Background:
- Pharmacological inhibitors targeting polycomb proteins aim to restore tumor suppressor gene expression but face limitations due to mutations in key transcriptional activators like TP53.
- Poor clinical outcomes of polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), hinder epigenetic monotherapy development.
Purpose of the Study:
- To develop a novel synthetic reader-actuator (SRA) for epigenome actuation by targeting polycomb chromatin.
- To investigate the SRA's ability to modulate core transcriptional activators and restore tumor suppressor gene expression in TNBC cells.
Main Methods:
- Epigenome actuation using a synthetic reader-actuator (SRA) designed to bind trimethylated histone H3 lysine 27.
- Utilizing TNBC BT-549 cells and spheroids to assess gene expression changes and phenotypic alterations.
Main Results:
- SRA expression in TNBC BT-549 cells led to a ≥2-fold upregulation of 122 genes, including those involved in cell death, cell cycle arrest, and migration inhibition.
- SRA-expressing spheroids exhibited reduced size and a loss of invasion in Matrigel, indicating inhibition of cancer cell invasiveness.
Conclusions:
- Targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and promote anti-cancer phenotypes.
- Further development of robust gene regulators like the SRA may offer therapeutic benefits for patients with triple-negative breast cancer.
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