Purposes: To identify tumor suppressor genes (TSGs) silenced by aberrant promoter methylation and discover new epigenetic biomarkers for early diagnosis and prognosis of renal cell carcinoma (RCC).Interferon regulatory factor 8 (IRF8),as a central element of IFN-γ-signaling,modulates multiple physiological processes and plays a critical role in tumor suppression.However,its expression and underlying molecular mechanism remain elusive in RCC.We explore its epigenetic alteration in RCC and analyze the possible clinicopathological association.Methods: We examined IRF8 expression and methylation in RCC cell lines and primary tumors by semi-quantitative RT-PCR,methylation-specific PCR and bisulfite genomic sequencing,and further assessed its tumor suppressive functions.Results: We found that IRF8 was widely expressed in human normal tissues including kidney,but frequently downregulated by promoter methylation in RCC cell lines.IRF8 methylation was detected in 25% of primary tumors,but not in adjacent non-malignant renal tissues,and associated with higher tumor nuclear grade of RCC.Ectopic expression of IRF8 inhibited colony formation and migration abilities of RCC cells,through inducing cell cycle G2/M arrest and apoptosis.IFN-γ,could induce IRF8 expression in RCC cells,together with increased cleaved-PARP.We further found that IRF8 inhibited expression of oncogenes YAP1 and survivin,as well as upregulated expression of tumor suppressor genes CASP1,p21 and PTEN.Conclusion: Our data demonstrate that IRF8 as a functional tumor suppressor is frequently methylated in RCC,indicating that IRF8-mediated interferon signaling is involved in RCC pathogenesis.