Metabolomics And Transcriptomics Profiles Reveal The Dysregulation Of The Tricarboxylic Acid Cycle And Related Mechanisms In Prostate Cancer

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.What's new?Although many studies have reported accelerated tricarboxylic acid (TCA) cycle in prostate cancer (PCa) cells, the underlying metabolic reprogramming and molecular mechanisms remain elusive. Here, the authors systematically investigated the molecular changes in TCA cycle through metabolomics and transcriptomics analysis of matched normal and PCa tissues. Fumarate and malate were found to be highly correlated with tumor progression and expression of related genes. Potential anaplerotic routes from pyruvate, glutamine catabolism, and BCAA degradation contributed to replenishing metabolites for TCA cycle. These observations provide new molecular insight into PCa carcinogenesis and may facilitate the development of new and effective therapeutic strategies.