BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

Biochemical Institute University of Kiel Kiel 24098 Germany

Bioinformatics Core Unit Swiss Institute of Bioinformatics Bellinzona 6500 TI Switzerland

CEITEC Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic

Center for Biomarker Research in Medicine CBmed GmbH Graz 8010 Austria

Center for Biomarker Research in Medicine Vienna Core Lab2 Medical University of Vienna Vienna 1090 Austria

Charité Universitätsmedizin Berlin Hematology Oncology and Tumor Immunology corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin 10117 Germany

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna 1090 Austria

Comprehensive Cancer Center Medical University Vienna Vienna 1090 Austria

Computational Oncology Unit Department of Oncology Istituto di Richerche Farmacologiche 'Mario Negri' IRCCS Milano 20156 Italy

Department of Biomedical Imaging and Image Guided Therapy Division of Nuclear Medicine Medical University of Vienna Vienna 1090 Austria

Department of Biomedical Sciences Malmö Universitet Malmö 206 06 Sweden

Department of Biosciences and Medical Biology Cancer Cluster Salzburg Paris Lodron University of Salzburg Salzburg 5020 Austria

Department of Cell Biology Charles University Prague Czech Republic and Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Vestec u Prahy Czech Republic

Department of Molecular Biology Umeå University Umeå 901 87 Sweden

Department of Nutritional Sciences Faculty of Life Sciences University of Vienna Vienna 1090 Austria

Department of Pathology Medical University of Vienna Vienna 1090 Austria

Experimental and Clinical Research Center a cooperation between the MDC and the Charité Berlin Germany

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Vienna 1210 Austria

Institute of Medical Biochemistry University of Veterinary Medicine Vienna Vienna 1210 Austria

Institute of Oncology Research Bellinzona and Faculty of Biomedical Sciences USI Lugano 6500 TI Switzerland

Institute of Physiology Pathophysiology and Biophysics University of Veterinary Medicine Vienna Vienna 1210 Austria

Max Delbrück Center for Molecular Medicine in the Helmholtz Association Group Biology of Malignant Lymphomas Berlin 13125 Germany

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna 1210 Austria

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Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment