title: 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.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong.
authors.forename: LiLi
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Qianling
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China. Electronic address: chen_gf@yahoo.com.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong. Electronic address: qtao@cuhk.edu.hk.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. Electronic address: jinjie@vip.163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D008297:Male; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000099185:Interferon Regulatory Factor-8
chemical_list: D001374:Azacitidine; D015254:DNA Modification Methylases; D000077209:Decitabine; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C012589:trichostatin A
keywords: Epigenetic; IRF8; Methylation; Renal carcinoma; Tumor suppressor