FACT is an accelerator of tumorigenesis, a marker of aggressive, undifferentiated cancers, and a potential therapeutic target
Garcia, Henry Alexander
MetadataShow full item record
Facilitates Chromatin Transcription (FACT) is a heterodimeric complex of subunits SSRP1 and Spt16 that is involved in chromatin remodeling during transcription, replication, and DNA repair. FACT was thought to be ubiquitously expressed and little was known about FACT function in the context of the whole organism, either in normal physiological conditions or in disease, including cancer. Our lab had previously discovered that a class of anticancer compounds called Curaxins inhibit FACT activity and that this caused activation of p53 and inhibition of NF-kB. Additionally, it was found that FACT was overexpressed in human tumor cell lines and in mouse mammary tumors. In this study we aimed to understand the role of FACT in mammalian organism in physiological conditions and in cancer. For this we measured FACT expression in mouse and human normal and diseased tissues using immunohistochemistry (IHC) staining and mRNA expression data from publically available microarray datasets. We found that FACT is not expressed at high or even detectable levels in most adult cells, but is highly expressed in embryo including embryonic stem cells. Based on our analysis of mRNA expression, co-staining with the proliferation marker Ki67, and experimental manipulation of cell differentiation and proliferation in vitro, we found that FACT expression is associated more with undifferentiated status of cells and not with proliferation, suggesting that FACT may play a role in maintenance of the undifferentiated state of cells. In line with this, we also found that FACT expression was reduced upon senescence of BJ and WI-38 fibroblasts by oncogene-induced senescence and etopiside, respectively. Our study of FACT expression and function in cancer revealed that FACT expression was strongly associated with poorly differentiated aggressive cancers with low survival rate. Additionally, FACT was found to be upregulated during in vitro transformation of mouse embryonic fibroblasts, human BJ fibroblasts, and human mammary epithelial cells and is be necessary, but not sufficient, for driving transformation. By measuring tumor cell response to FACT knockdown using RNAi approach we observed that, FACT is required for the survival and growth of tumor cells, but not normal cells. Genome-wide mapping of FACT chromatin-binding using ChIP-sequencing approach suggested FACTs role in selective chromatin remodeling of genes that stimulate proliferation, inhibit cell death and differentiation, and regulate cellular stress response. These findings shed light upon the physiological role of FACT and suggest that FACT may be a marker of aggressive cancer as well as provide more support for FACT as a promising target for anticancer therapy.