AU Cara Shields
Research – bioRxiv – PIC recruitment by synthetic reader-actuators to polycomb-silenced genes blocks triple-negative breast cancer invasion
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.
Review – Trends in Biochem Sci – Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering
Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering
Franklin KA, Shields C, Haynes KA. (2022) Trends Biochem Sci. 47: 417–432. Free access (until June 3, 2022)
PMID: 35267540 | PMCID: PMC9074927
Epigenetics is a process where changes in gene expression are inherited through cell divisions and in some cases across familial generations. As more links between epigenetics and human development and disease have emerged, scientists have become more interested in controlling epigenetic states using molecular technologies including protein engineering. In this review, we discuss a relatively new substrate for epigenetic engineering, a class of gene regulators called “reader-effectors.” These are different from DNA-binding transcription factors in that a single reader-effector type can engage at multiple sites through interactions with biochemical marks (“signals”) on chromatin, the protein/DNA structure that organizes the genome. So far, scientists have used “epigenome editing” to generate or erase signals to alter epigenetic states. Relatively little has been done to control how these signals are transduced into outputs, such as gene regulation, to ultimately control cell behavior. We discuss what natural systems have taught us about the mechanism of two basic composable parts, the “reader” and “effector” domains, and discuss potential of reader-effector engineering, a technique we call “epigenome actuation.”
Research – RETM – Differential epigenetic effects of BMI1 inhibitor PTC-028 on fusion-positive rhabdomyosarcoma cell lines from distinct metastatic sites
Differential epigenetic effects of BMI1 inhibitor PTC-028 on fusion-positive rhabdomyosarcoma cell lines from distinct metastatic sites
Shields C, Schnepp RW, Haynes KA. (2022) Regen Eng Transl Med. https://doi.org/10.1007/s40883-021-00244-9
Previously, we reported in “Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target” that genetic and pharmacologic inhibition of BMI1 reduces the viability of alveolar rhabdomyosarcoma (ARMS) cells, suggesting a new treatment option for patients with the rare pediatric cancer fusion-positive rhabdomyosarcoma (FP-RMS). In a follow-on study, we identified gene expression changes that underlie the loss of cell viability and proliferation, and addressed some open questions about the affect of BMI1 inhibition on ARMS. For instance, in our previous study, BMI1 inhibition affected phosphorylation of LATS1/2, but BMI1 is a transcriptional regulator, not a kinase or phosphatase. In the new study, through RNA-sequencing we found that the mRNA levels of two kinases EPHA2 and PDGFRA were affected during BMI1 inhibition, revealing a possible gene regulation link between BMI1 and kinases that target LATS1/2. RNA-seq also revealed transcription profile differences between ARMS cells derived from two different sites (metastases to an axillary lymph node and bone marrow). Despite this heterogeneity, epigenetic intervention (BMI1 inhibition) induces an anti-cancer response.
Research – Molecular Oncology – Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
Shields CE, Potlapalli S, Cuya-Smith SM, Chappell SK, Chen D, Martinez D, Pogoriler J, Rathi KS, Patel SA, Oristian KM, Linardic CM, Maris JM, Haynes KA, Schnepp RW. (2021) Molecular Oncology.
PMID: 33523558
Abnormal expression and behavior of chromatin proteins occurs in many types of cancer, so scientists have investigated these proteins as possible drug targets. Treatment of alveolar rhabdomyosarcoma (ARMS) remains a major therapeutic challenge in pediatric oncology. In this collaboration of the Schnepp and Haynes labs, we demonstrate that genetic and pharmacologic inhibition of BMI1 reduces ARMS viability. We show that BMI1 inhibits the tumor suppressive Hippo pathway and, conversely, that BMI1 disruption upregulates Hippo signaling. Collectively, these findings provide an initial framework for targeting BMI1 in ARMS and additional sarcomas.
Haynes Lab | Emory 