AU Natecia Williams

Research – bioRxiv – PIC recruitment by synthetic reader-actuators to polycomb-silenced genes blocks triple-negative breast cancer invasion

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SRA_TNBC_2023_thumbPIC recruitment by synthetic reader-actuators to polycomb-silenced genes blocks triple-negative breast cancer invasion
Williams NL, Hong L, Jaffe M, Shields CE, Haynes KA. (2023) bioRxiv.

An exciting new approach for cancer therapy is to turn on genes within the cancer cells that can stop them from growing and spreading. This approach, called epigenetic therapy, uses small molecules (inhibitors) to block chromatin-modifying proteins that play a role in silencing anti-cancer genes. However, this approach has shown disappointing results in clinical trials for solid cancers, perhaps due to biological limitations. For example, inhibitors can accidentally activate the proteins they are supposed to block (e.g. EZH inhibitors promote EZH2/FOXM1 complexes, Mahara et al 2016), and inhibitors can’t turn on important gene-regulating proteins that are damaged in many cancers. To overcome these limitations we have developed a new tool, synthetic reader-actuators (SRAs), that directly targets chromatin-silenced regions, activates the pre-initiation complex (PIC), and turns on gene transcription. In this report we tested SRAs in triple negative breast cancer cells (BT-549) and identified 122 activated genes. SRA-expressing BT-549 cells showed reduced spheroid size over time, loss of invasion, and activation of apoptosis. While epigenetic drugs have not been successful in many clinical trials, by using synthetic proteins we showed that robust epigenetic reprogramming is possible in cells from solid cancers.

Commentary – Nature SMB – Chromatin engineering offers an opportunity to advance epigenetic cancer therapy

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Chromatin engineering offers an opportunity to advance epigenetic cancer therapy
Baskin NL, Haynes KA. (2019) Nature Struct Mol Biol. 26: 842-845.
PMID: 31582843

After scientists had discovered that DNA damage is linked to cancer, further research revealed an additional culprit: the misregulation of normal, undamaged genes. DNA folding is a highly regulated process in which a DNA-RNA-protein network called chromatin ensures that genes are switched on and off in the appropriate time and place. In cancer, this process often becomes misregulated to the advantage of the cancer cell, allowing cancer cells to grow unchecked, evade anti-cancer drugs, and generate new tumors. This discovery has enabled scientists to develop a new class of cancer treatment called epigenetic therapy, which targets misregulated chromatin and therefore works differently at the molecular level compared to more traditional chemotherapies (e.g. cisplatin). In our commentary we discuss how protein engineering could be used to further advance epigenetic therapy so that it is more effective against difficult-to-treat cancers.