Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is Epigenetically Activated in Luminal Epithelial Cells in Prostate Cancer

The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas. We focused on key effectors of TLR signaling, the Myddosome-complex components IRAK1, IRAK4 and MYD88 (myeloid differentiation primary response 88), and TRAF6 (tumor-necrosis-factor receptor associated factor 6). In PCa, -mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas and were predominantly expressed in leukocytes, and , in endothelial cells. Compared to NOR, only was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p<2x10), whereas the expression of , , and was unchanged in PCa, and -expression was inversely correlated with a specific differentially methylated region (-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r<-0.36; Fisher's test, p<10). Transcription factors with high binding affinities in -DMR were significantly enriched for canonical pathways associated with viral infection and carcinogenic transformation in the Kyoto Encyclopedia of Gene and Genomes analysis. DU145 cells, exhibiting hypermethylated -DMR and low -expression, reacted with 4-fold increased -expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated -DMR and high endogenous -mRNA levels, responded with strong activation of -expression to UTI89 infection. In summary, exclusive overexpression of was observed in luminal epithelial cells in PCa, suggesting it has a role in addition to Myddosome-dependent TLR signaling. Our data show that the endogenous epigenetic status of PCa cells within -DMR is decisive for expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.