JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression

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, CCL3 and CCL8 in Pten -deficient prostates. Strikingly, JUN depletion reversed both, senescence and senescence-associated immune cell infiltration and consequently 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. ### Competing Interest Statement The authors have declared no competing interest. * AP-1 : Activator protein-1 AR : Androgen receptor BCR : Biochemical recurrence CRPC : Castration resistant prostate cancer DEG : Differentially expressed gene EpCAM : Epithelial cell adhesion molecule FDR : False discovery rate FFPE : Formalin-fixed paraffin embedded GO : Gene ontology GSEA : Gene set enrichment analysis H&E : Hematoxylin and eosin HR : Hazard ratio IHC : Immunohistochemistry IF : Immunofluorescence JNK : JUN N-terminal kinase MsigDB : molecular signature database NEPC : Neuroendocrine prostate cancer NES : Normalized enrichment score OIS : Oncogene induced senescence PIN : Prostatic intraepithelial neoplasia PICS : PTEN-loss induced cellular senescence PbCre : Probasin Cre PCa : Prostate cancer PCA : Principal component analysis PE : Prostate epithelium PI3K : Phosphoinositide 3-kinase PTEN : Phosphate and Tensin Homologue RFS : Relapse free survival RNA-seq : RNA sequencing RPPA : Reverse-phase protein array SASP : Senescence-associated secretory phenotype STAT3 : signal transducer and activator of transcription 3 TAM : Tumor-associated macrophage TAN : Tumor-associated neutrophil TCGA-PRAD : Cancer Genome Atlas Prostate Adenocarcinoma TF : transcription factor TMA : Tissue microarray TME : Tumor microenvironment