Epigenetic regulation of the Birc5 promoter explains mechanism of action of YM‐155 in synovial sarcoma

Abstract

YM‐155 is an anti‐cancer therapy that has advanced into 11 different human clinical trials to treat various cancers. This apoptosis‐inducing therapy indirectly affects the protein levels of Survivin (Gene: Birc5), but the molecular underpinnings of the mechanism remain largely unknown. Synovial sarcoma is another cancer with high protein expression of Survivin. We investigated whether YM‐155 would be a viable therapeutic option to treat synovial sarcoma. We, therefore, applied YM‐155 therapy to human synovial sarcoma cell lines and a genetically engineered mouse model of synovial sarcoma. We discovered that YM‐155 exhibited nanomolar potency against human synovial sarcoma cell lines and the treated mice with synovial sarcoma demonstrated a 50% reduction in tumor volume compared to control treated mice. We further investigated the mechanism of action of YM‐155 by looking at the change of modifications of the histone tails that were near the Birc5 promoter. Using chomatin immunoprecipitation (ChIP) we discovered that the histone epigenetic marks of H3K27 for the Birc5 promoter changed upon YM‐155 treatment. H3K27me3 increased whereas the H3K27ac decreased, highlighting the decrease of the protein Survivin occurs through epigenetic silencing of the gene's promoter. The treatment of YM‐155 was accompanied by an increase in NFkB protein expression, which indicates an attempt of the cell to initiate a positive feedback due to the decrease in Survivin expression. This combination of molecular events eventually resulted in Caspace 3/7/8 upregulation and death of the sarcoma cells.Support or Funding InformationAlex's Lemonade StandIdaho State University Start UpThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.