Abstract 1753: Deregulation and therapeutic potential of targeting IRAK3 as chronic inflammation suppressor in prostate cancer

Abstract

Chronic inflammation is emerging as a targetable driver of tumorigenesis. During chronic inflammation, several inflammatory molecules are either activated or suppressed for a prolonged time. The oncogenic role of many of these inflammatory genes in prostate cancer (PCa) remains unexplored despite the increasing association of chronic inflammation with PCa initiation, progression, and therapy resistance in the scientific literature. The overarching goal of this study was to identify deregulated inflammatory suppressor genes, including interleukin-1 receptor-associated kinases 3 (IRAK3) as biomarkers for inflammation-driven PCa aggressiveness or progression. To achieve this, we utilize cutting-edge integrative (epi)genomic and transcriptomic techniques to investigate the role of IRAK3 in PCa progression, as well as the therapeutic potential of targeting IRAK3 in PCa. An array of computational tools was deployed to analyze Illumina HumanMethylation450K and whole exome RNAseq clinical datasets acquired from TCGA and cBioportal databases to identify differentially methylated and altered or expressed inflammatory suppressor genes in PCa patients/samples. We identified six inflammatory suppressor genes (IRAK3, TOLLIP, SOCS1, RNF216, IL1RL1, and TNFAIP3) to be significantly deregulated in indolent (n=493), metastatic (n=212), and lethal (n=50) PCa patients/samples. The expression patterns of these genes were correlated with clinical traits, such as age, progression-free status, overall survival status, biochemical recurrence, pathology as well as metastatic status using weighted gene co-expression network analysis, which identified IRAK3 as one of the top genes to explore. MutSigCV and GISTIC tools were used to identify somatic mutations and copy-number alterations. IRAK3 was found to be downregulated in most indolent, metastatic and lethal PCa samples. Its low expression correlated significantly with the progression, metastatic and recurrence statuses of the PCa. The genome-wide DNA methylation analysis of the 16 CpG probes identified in IRAK3 reveals hypermethylation (b-value or m-value < 0.01) at the promoter regions, which may be responsible for the observed transcriptional repression of IRAK3. Further analysis shows that DNA methylation is higher in PCa samples with mutated IRAK3 compared to those without the mutation. Mechanistic studies using genome-wide CRISPR-Cas9 gene-editing techniques were performed to create IRAK3+/+ or IRAK3-/- PCa clones. Using a series of bioassays, IRAK3 reactivation was found to inhibit PCa cell proliferation, migration, colony formation, and chemoresistance as well as induce apoptotic cell death. IRAK3+/+ PCa cells responded well to Taxane analogs compared to IRAK3-/- PCa cells. In conclusion, we have been able to demonstrate the tumor suppressor potential of IRAK3 in prostate cancer cells. Citation Format: Saheed Oluwasina Oseni, Corey Naar, Magdalah Philemy, Genesis Acosta Laguer, Faika Ambrin, Sharlanda Metayer, Ariana Perez, Javoncia Betty, Preethika Praveen, James Hartmann, Mirjana Pavlovic, James Kumi-Diaka. Deregulation and therapeutic potential of targeting IRAK3 as chronic inflammation suppressor in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1753.

The Molecular Basis and Clinical Consequences of Chronic Inflammation in Prostatic Diseases: Prostatitis, Benign Prostatic Hyperplasia, and Prostate Cancer

“…The majority of these studies have also neglected the tumor-promoting potentials of midstream proteins, which act as inflammatory regulators and adapters for upstream and downstream mediators of inflammation [ 110 , 111 ]. Hence, the overarching goal of our research group is to investigate and elucidate the oncogenic role of the less-studied midstream regulatory and adaptor proteins in the inflammatory cascade, particularly the role of interleukin-1 receptor-associated kinases (IRAKs) in prostate tumor progression, as well as to gain insight into their diagnostic, prognostic, and therapeutic potentials in chronic inflammation-driven PCa [ 112 , 113 , 114 ]. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are alarming molecules involved in the initiation of the inflammatory cascade expressed by pathogens (microbes) and damaged/dying cells or their intracellular components, respectively [ 115 ].…”