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| Item Type: | Article |
|---|---|
| Title: | JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression |
| Creators: |
Redmer, T.  ORCID: https://orcid.org/0000-0002-0050-9478, Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtova, K., Kodajova, P., Högler, S., Schlederer, M., Stoiber, S., Oberhuber, M., Bolis, M., Neubauer, H.A., Miranda, S., Tomberger, M., Harbusch, N.S., Garces de Los Fayos Alonso, I., Sternberg, F., Moriggl, R., Theurillat, J.P., Tichy, B., Bystry, V., Persson, J.L., Mathas, S. ORCID: https://orcid.org/0000-0001-9626-1413, Aberger, F., Strobl, B., Pospisilova, S., Merkel, O., Egger, G., Lagger, S. and Kenner, L.
|
| Abstract: | 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-1ß production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1ß 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-1ß, TNF-a, 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. |
| Keywords: | Prostate Cancer, AP-1 Transcription Factors, JUN, Senescence, SASP, Immune Infiltration, Animals, Mice |
| Source: | Molecular Cancer |
| ISSN: | 1476-4598 |
| Publisher: | BioMed Central |
| Volume: | 23 |
| Number: | 1 |
| Page Range: | 114 |
| Date: | 29 May 2024 |
| Official Publication: | https://doi.org/10.1186/s12943-024-02022-x |
| PubMed: | View item in PubMed |
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