Abstract 5273: Multi-omics approaches reveal potential role for corticosterone in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer in American men. In 2018, 164,690 new cancer cases and 29,430 cancer deaths are projected to occur in the United States. Currently, there is no efficient diagnostic and safe treatment option for the management of PCa. Using Ultra-High Performance Liquid Chromatography coupled High Resolution Mass Spectrometry (UHPLC-HRMS), we globally profiled more than 1400 metabolites across 79 urine samples related to PCa (19 control, 23 benign prostate hyperplasia (BPH), 11 prostatitis, and 26 PCa samples). Among all, corticosterone was identified as a top differential metabolite. Corticosterone levels were markedly elevated in PCa urine samples and modest but significant elevation of the corticosterone in BPH and prostatitis urine samples compared to controls, with an excellent area under the receiver operating characteristic curve of 0.95, 0.94, and 0.93, respectively. In addition, the expression of corticosterone biosynthetic gene, Steroid 11-beta-hydroxylase (CYP11B1), was elevated in PCa tissues, cell lines, and urine samples, while Corticosteroid 11-beta-dehydrogenase isozyme 2 (HSD11B2), which metabolize corticosterone, were markedly reduced in prostate tumors. With the understanding that androgen signaling is the key factor for prostate cancer, we investigated the role of androgen in regulating CYP11B1 and HSD11B2. We analyzed several androgen treated PCa cell lines derived global gene expression datasets and revealed that treatment with androgen increase in CYP11B1 expression and a concomitant decrease in HSD11B2 expression levels. Interestingly, we uncover that genetic knockdown of Androgen Receptor (AR) diminished CYP11B1 expression and alternatively, increased HSD11B2. Moreover, AR based chromatin occupancy (ChIP-seq) data also suggest direct binding of AR to the promoter of CYP11B1 in multiple PCa cells. The role of corticosterone in PCa is previously unknown. Our multi-omics approaches thus indicate that corticosterone might be potential prognostic marker for PCa. The tumor biology and mechanism through which corticosterone associates with PCa is being investigated in our laboratory. Citation Format: Iqbal Mahmud, Bongyong Lee, Ranjan Perera, Timothy J. Garrett. Multi-omics approaches reveal potential role for corticosterone in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5273.