AUTHOR=Schagdarsurengin Undraga , Breiding Vanessa , Loose Maria , Wagenlehner Florian , Dansranjav Temuujin 

TITLE=Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.991368

DOI=10.3389/fonc.2022.991368

ISSN=2234-943X

ABSTRACT=<p>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 <italic>in vitro</italic> 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, <italic>IRAK1</italic>-mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas <italic>IRAK4</italic> and <italic>MYD88</italic> were predominantly expressed in leukocytes, and <italic>TRAF6</italic>, in endothelial cells. Compared to NOR, only <italic>IRAK1</italic> was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p&lt;2x10<sup>-8</sup>), whereas the expression of <italic>IRAK4</italic>, <italic>MYD88</italic>, and <italic>TRAF6</italic> was unchanged in PCa, and <italic>IRAK1</italic>-expression was inversely correlated with a specific differentially methylated region (<italic>IRAK1</italic>-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r&lt;-0.36; Fisher’s test, p&lt;10<sup>-10</sup>). Transcription factors with high binding affinities in <italic>IRAK1</italic>-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 <italic>IRAK1</italic>-DMR and low <italic>IRAK1</italic>-expression, reacted with 4-fold increased <italic>IRAK1</italic>-expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic <italic>Escherichia coli</italic> strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated <italic>IRAK1</italic>-DMR and high endogenous <italic>IRAK1</italic>-mRNA levels, responded with strong activation of <italic>IRAK1</italic>-expression to UTI89 infection. In summary, exclusive overexpression of <italic>IRAK1</italic> 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 <italic>IRAK1</italic>-DMR is decisive for <italic>IRAK1</italic> expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.</p>