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-γ. Although STAT1 is a key mediator of the IFN-γ 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 a murine model 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 promoter was 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 in DSS. In addition, uSTAT1 levels were negatively correlated with 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 and Bad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis. Together, our findings show how 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.
Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Mary A
MA
Zimmerman
Nur-Taz
NT
Rahman
Dafeng
D
Yang
Guy
G
Lahat
Alexander J
AJ
Lazar
Raphael E
RE
Pollock
Dina
D
Lev
Kebin
K
Liu
D000818:Animals; D017209:Apoptosis; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis; D051025:bcl-Associated Death Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D050794:STAT1 Transcription Factor; D051025:bcl-Associated Death Protein; D019014:fas Receptor