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

Posted on January 31, 2023 Updated on April 21, 2023

PIC 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. https://www.biorxiv.org/content/10.1101/2023.01.23.525196v1

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.