The xanthine oxidoreductase gene (XOR) encodes an important source of reactive oxygen species and uric acid, and its expression is associated with various human diseases including several forms of cancer. We previously reported that basal human XOR (hXOR) expression is restricted or repressed by E-box and TATA-like elements and a cluster of transcriptional proteins, including AREB6-like proteins and DNA-dependent protein kinase (DNA-PK). We now demonstrate that the cluster contains the tumor suppressors SAFB1, BRG1, and SAF-A. We further demonstrate that SAFB1 silencing increases hXOR expression and that SAFB1 directly binds to the E-box. Multiple studies in vitro and in vivo including pulldown, immunoprecipitation and chromatin immunoprecipitation analyses indicate that SAFB1, Ku86, and BRG1 associate with each other. The results suggest that the SAFB1 complex binds to the hXOR promoter in a chromatin environment and plays a critical role in restricting hXOR expression via its direct interaction with the E-box, DNA-PK, and tumor suppressors. Moreover, we demonstrate that the cytokine, oncostatin M (OSM), induces the phosphorylation of SAFB1 and that the OSM-induced hXOR mRNA expression is significantly inhibited by silencing the DNA-PK catalytic subunit or SAFB1 expression. The present studies for the first time demonstrate that hXOR is a tumor suppressor-targeted gene and that the phosphorylation of SAFB1 is regulated by OSM, providing a molecular basis for understanding the role of SAFB1-regulated hXOR transcription in cytokine stimulation and tumorigenesis.