Aberrant expression of various glycolytic enzyme genes is significantly associated with prostate cancer progression and survival outcomes, according to a recent systematic analysis.
Prostate cancer (PCa) is the second-leading cause of cancer death in men. Recent studies showed that alterations in metabolic pathways are involved in PCa development and progression.
A study in the American Journal of Clinical and Experimental Urology assessed the expression profiles of genes encoding glycolytic enzymes in relation to PCa disease progression and survival outcomes. This systematic analysis utilized The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) RNA sequencing dataset derived from primary tumor tissues.
Prostate Cancer Biomarkers and Expression Patterns
All the genes encoding glycolytic enzymes and their isoforms were analyzed. Of 25 genes, 10 demonstrated very low-level expression in both benign and malignant tissues, suggesting their insignificance for PCa. Four genes, HK2/GPI/PFKL/PGAM5, demonstrated a significantly higher mRNA level in the malignant versus benign prostatic tissues. Conversely, nine genes, HK1/GCK/PFKM/PFKP/ALDOC/PGK1/PGAM1/ENO2/PKM, demonstrated a significantly lower mRNA level in the malignant versus benign prostatic tissues.
Further analysis revealed that three genes, ENO2/GPI/GCK, showed a significantly higher area under the curve value on receiver operating characteristic (ROC) curve analysis, indicating a potential biomarker value.
GPI and ALDOC showed significantly increased expression with higher prostate-specific antigen levels, but only GPI expression was significantly related to disease progression and disease-specific survival. Increased ENO2 expression was linked to progression-free interval, lymph node invasion, and Gleason scores. Conversely, reduced GCK expression was associated with lymph node invasion.
GPI Gene Emerges as a Key Prognostic Factor in Prostate Cancer
As GPI demonstrated the most significance concerning disease progression and survival, it was further investigated using the Kaplan–Meier curve analysis. The results showed a significant association between higher GPI expression levels and both progression-free interval and disease-specific survival. On calculating a 10-year prediction among the four highly altered genes, GPI demonstrated the highest predicting value for progression-free interval (ROC: 0.76) and disease-specific survival (ROC: 0.979). These results highlight the potential of GPI expression as a novel prognostic factor for PCa patients.
Multiple Glycolytic Genes Show Significant Upregulation in Patients
Eight glycolytic genes, GPI/HK3/PFKL/ALDOA/ALDOB/ENO2/ENO3/PKM, showed a significant upregulation in patients with disease relapses versus those without relapses after initial treatment. Moreover, six genes, GPI/PFKL/ALDOA/TPI1/GAPDH/ENO1, were highly upregulated in patients with biochemical relapse, of which GPI/PFKL/ALDOA were also upregulated in patients with clinical disease relapse. These results highlight the potential role of GPI and PFKL upregulation in PCa progression.
PFKL and PGAM5 Linked to Castration Resistance
Castration-resistant status (CRPC) and neuroendocrinal status (NEPC) are incurable, lethal types of metastatic PCa. PFKL and PGAM5 positively correlated with two critical CRPC factors (androgen receptor (AR) score and AR splice variant-7 expression) but negatively correlated with NEPC score. An androgen-dependent mechanism was confirmed for regulating PFKL/PGAM5 expression in PCa, as their expression was suppressed with AR inhibitors and in LuCaP35 xenograft tumors after animal castration.
In contrast, HK3/GCK/PKLR genes positively correlated with NEPC score but negatively correlated with the two CRPC factors, comparable to the NEPC marker ENO2. Further analysis revealed that ENO2/GCK/PKLR but not HK3 genes showed highly increased expression in neuroendocrine PCa versus adenocarcinomas, indicating the potential of GCK/PKLR as a novel NEPC biomarker.
Xu, H., Liu, W., He, C., Mirza, M., & Li, B. (2023). Aberrant expression of multiple glycolytic enzyme genes is significantly associated with disease progression and survival outcomes in prostate cancers. American journal of clinical and experimental urology, 11(6), 530–541. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10749383/