Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer

Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0–10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0–10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. Prostate cancer (PCa) 1The abbreviations used are:PCaprostate cancerPCTprostate cancer tissueANTadjacent noncancerous tissueLC-MSliquid chromatography-mass spectrometryMTBEmethyl tert-butyl etherPSAprostate-specific antigenPCAprinciple component analysisSAHS-adenosylhomoserineMTA5-methyltioadenosineSAMS-adenosylmethionineNMNnicotinamide mononucleotideNADnicotinamide adenine dinucleotideNADPnicotinamide adenine dinucleotide phosphateGlcN-6-PD-glucosamine 6-phosphateGlcNAcN-acetyl-D-glucosamineGlcNAc-6PN-acetyl-D-glucosamine 6-phosphateUDP-GlcNAcUDP-acetyl-glucosamineHBPhexosamine biosynthesis pathwayOGTO-linked N-acetyl-glucosamine transferaseBPHbenign prostatic hyperplasiaS1Psphingosine-1-phosphate. is the most commonly diagnosed visceral malignancy among men and the second leading cause of cancer-related death in Western countries, second only to lung cancer (1.Sharma S. Imaging and intervention in prostate cancer: Current perspectives and future trends.Indian J. Radiol. Imaging. 2014; 24: 139-148Crossref PubMed Scopus (19) Google Scholar, 2.Singh A.P. Bafna S. Chaudhary K. Venkatraman G. Smith L. Eudy J.D. Johansson S.L. Lin M.F. Batra S.K. Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells.Cancer Lett. 2008; 259: 28-38Crossref PubMed Scopus (76) Google Scholar). The prevalence of PCa in Asian populations, such as China and Japan, was much lower than Western countries, but its incidence and associated mortality rates are increasing rapidly with the growing aging population (3.Hsing A.W. Tsao L. Devesa S.S. International trends and patterns of prostate cancer incidence and mortality.Int. J. Cancer. 2000; 85: 60-67Crossref PubMed Scopus (699) Google Scholar). Barriers in the effective clinical management of PCa include significant intratumoral heterogeneity and limited knowledge of the molecular events governing tumor progression (4.Ding Z. 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