Molecular and Cellular Pathobiology Unphosphorylated STAT1 Promotes Sarcoma Development through Repressing Expression of Fas and Bad and Conferring Apoptotic Resistance

STAT1 exists in phosphorylated (pSTAT1) and unphosphorylated (uSTAT1) forms each regulated by IFN-g . Although STAT1 is a key mediator of the IFN-g signaling pathway, an essential component of the host cancer immunosurveillance system, STAT1 is also overexpressed in certain human cancers where the functions of pSTAT1 and uSTAT1 are ill defined. Using amurinemodel of soft tissue sarcoma (STS), we show that disruption of the IFN effector molecule IRF8 decreases pSTAT1 and increases uSTAT1 in STS cells, thereby increasing their metastatic potential.We determined that the IRF8 gene promoterwas hypermethylated frequently in human STS. An analysis of 123 human STS specimens revealed that high uSTAT1 levels in tumor cells was correlated with a reduction in disease-specific survival (DSS), whereas high pSTAT1 levels in tumor cells were correlated with an increase inDSS. In addition, uSTAT1 levels were negatively correlatedwith pSTAT1 levels in these STS specimens. Mechanistic investigations revealed that IRF8 suppressed STAT1 transcription by binding the STAT1 promoter. RNAi-mediated silencing of STAT1 in STS cells was sufficient to increase expression of the apoptotic mediators Fas andBad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis. Together, ourfindings showhow the phosphorylation status of pSTAT1 determines its function as a tumor suppressor, with uSTAT1 acting as a tumor promoter that acts by elevating resistance to Fas-mediated apoptosis to promote immune escape. Cancer Res; 72(18); 4724–32. 2012 AACR.