Specific Inactivation of CIC-DUX4/P300/CBP Transcriptional Complex Impairs CIC-DUX4 Sarcoma Cell Viability
CIC-DUX4 sarcoma (CDS) is metastatic and aggressive, primarily affecting children and young adults. The prognosis remains poor for those diagnosed, resulting in a need for continued research of therapeutic methods. The morphology of CDS is similar to Ewing sarcoma, as it is a member of the undifferentiated round cell sarcoma family. Oncogenesis in CIC-DUX4 requires two histone acetyl transferases: E1A-binding protein (P300) and cyclic AMP response element-binding protein (CBP). Considering this, inhibition of P300/CBP binding should hinder oncogenesis. This project tests the effectiveness of P300/CBP inhibitors on Kitra-SRS and NCC-CDS-X1, two CDS cell lines. Initially, the effects of continuous treatment were studied through induction of the cells with the P300/CBP inhibitors. The results were quantified by immunostaining of nuclei (via DAPI) and Ki-67, a protein indicative of proliferation. The continuous treatment displayed effectiveness, prompting a pulse experiment to assess recovery utilizing the same method of analysis. One compound exhibited a high degree of effectiveness with two others displaying diminished effects in comparison. To assess specificity of the P300/CBP inhibitors, PANC-1, a pancreatic adenocarcinoma, and HCT-116, a colonic epithelial cell line were treated for 48 hours and compared to CDS via an ATP assay. This study shows that P300/CBP inhibitors target viability of CIC-DUX4 sarcoma in a specific manner thus, providing a possible approach for therapeutic applications in the future.