Prevention of chromatin destabilization by FACT is crucial for malignant transformation

Abstract

Expression of histone chaperone FACT is increased in tumors and associated with poor prognosis. We investigated why aggressive tumor cells need FACT using a model where FACT could be turned off and confirmed that while FACT is not essential for non-tumor cells, cells become dependent on FACT following oncogene-induced transformation. We compared the phenotypic and transcriptional changes induced by FACT loss and excluded a direct role for FACT in the transcription of genes essential for the viability of transformed cells. Moreover, we established that in immortalized and transformed cells, FACT has a weak negative effect on gene expression. At the same time, we observed a positive correlation between FACT enrichment and the rate of transcription, which was consistent with previous reports. To explain these puzzling observations, we hypothesized that FACT does not facilitate transcription elongation in transformed cells, but prevents nucleosome loss associated with transcription. Indeed, we observed destabilization of chromatin in immortalized and transformed cells upon FACT loss. Furthermore, transformed cells had less stable chromatin than non-transformed cells, which made them vulnerable to FACT loss. However, the mechanisms of cell death upon chromatin destabilization needs to be established. Our data suggest that malignant transformation is accompanied by general chromatin destabilization, and FACT prevents irredeemable chromatin loss.