Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis.

Abstract

Interferon regulatory factor 8 (IRF8), as a central element of IFN-γ-signaling, plays a critical role in tumor suppression. However, its expression and underlying molecular mechanism remain elusive in renal cell carcinoma (RCC). Here, we examined IRF8 expression and methylation in RCC cell lines and primary tumors, and further assessed its tumor suppressive functions. 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. Collectively, our data demonstrate that IRF8 as a functional tumor suppressor is frequently methylated in RCC, and IRF8-mediated interferon signaling is involved in RCC pathogenesis.

• Authors: Qian Zhang, Lian Zhang, LiLi Li, Zhaohui Wang, Jianming Ying, Yu Fan, Ben Xu, Lu Wang, Qianling Liu, Guangfu Chen, Qian Tao, Jie Jin
• Journal: Cancer letters (Cancer Lett) Vol. 354 Issue 2 Pg. 227-34 (Nov 28 2014) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25109451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Interferon Regulatory Factors
• interferon regulatory factor-8
• trichostatin A
• Decitabine
• DNA Modification Methylases
• Azacitidine

Topics

• Azacitidine (analogs & derivatives, pharmacology)
• Carcinoma, Renal Cell (genetics, immunology, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• DNA Methylation
• DNA Modification Methylases (antagonists & inhibitors)
• Decitabine
• Down-Regulation
• Female
• G2 Phase Cell Cycle Checkpoints (genetics)
• Genes, Tumor Suppressor
• HEK293 Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Interferon Regulatory Factors (biosynthesis, genetics, immunology)
• Kidney Neoplasms (genetics, immunology, pathology)
• M Phase Cell Cycle Checkpoints (genetics)
• Male
• Prognosis
• Promoter Regions, Genetic