title: A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors.
abstract: Both STAT3 and NF-κB are persistently activated in diverse cancers and promote tumor cell proliferation, survival, angiogenesis, and metastasis through transcriptional activation of multiple common genes. Paradoxically, STAT3 also suppresses many NF-κB-inducible genes involved in innate and adaptive antitumor immunity in spite of elevated levels of NF-κB in tumors. In this study, we show that expression of many NF-κB downstream target genes in tumors depends on STAT3 DNA binding. When STAT3 is elevated in tumor cells and tumor-infiltrating immune cells, persistently activated NF-κB interacts with STAT3 and preferentially binds to genes with STAT3-binding site(s) in promoters. A large number of NF-κB downstream genes associated with oncogenesis and chronic inflammation contain STAT3 DNA-binding site(s). However, in contrast, many genes frequently associated with antitumor immunity lack STAT3 DNA-binding site(s) and can only be activated by NF-κB when STAT3 is inhibited in tumors. The introduction of STAT3 DNA-binding sequences by site-specific mutagenesis in an immunostimulatory gene promoter allows its transcriptional activation by NF-κB in tumor cells. Furthermore, STAT3 facilitates NF-κB binding to genes that are important for tumor growth while inhibiting its binding to Th-1 immunostimulatory genes in growing tumors, including in tumor-infiltrating immune cells. The results of this study provide insight into how some of the oncogenic/inflammatory and Th-1 immunostimulatory genes are differentially regulated in cancer.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001665:Binding Sites; D048708:Cell Growth Processes / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D004273:DNA, Neoplasm; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human