JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression.
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Redmer Torben, Raigel Martin, Sternberg Christina, Ziegler Roman, Probst Clara, Lindner Desiree, Aufinger Astrid, Limberger Tanja, Trachtova Karolina, Kodajova Petra, Högler Sandra, Schlederer Michaela, Stoiber Stefan, Oberhuber Monika, Bolis Marco, Neubauer Heidi A, Miranda Sara, Tomberger Martina, Harbusch Nora S, Garces de Los Fayos Alonso Ines, Sternberg Felix, Moriggl Richard, Theurillat Jean-Philippe, Tichy Boris, Bystry Vojtech, Persson Jenny L, Mathas Stephan, Aberger Fritz, Strobl Birgit, Pospisilova Sarka, Merkel Olaf, Egger Gerda, Lagger Sabine, Kenner Lukas
Аннотация
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.