Abstract
BACKGROUND: Cancer cells exhibit altered metabolism whereby glucose is preferentially utilized to produce lactate through aerobic glycolysis. The increase in lactate production creates an acidic microenvironment that supports tumor progression and metastasis. Human small leucine zipper protein (sLZIP) is involved in the transcriptional regulation of genes related to migration and invasion of prostate cancer. However, the role of sLZIP in modulating glucose metabolism in prostate cancer remains unknown. This study investigates whether sLZIP regulates the transcription of glycolysis-related genes to promote metabolic reprogramming in prostate cancer. METHODS: Depletion of sLZIP resulted in the downregulation of several glycolytic genes, including glucose transporter 1, phosphofructokinase liver type, phosphoglycerate kinase 1 (PGK1), and lactate dehydrogenase. Among these, only PGK1 showed a prominent dose-dependent decrease in mRNA and protein expression after sLZIP silencing. RESULTS: Mechanistically, increasing or decreasing sLZIP affected the promoter activity of PGK1 in a similar manner. Moreover, the absence of sLZIP attenuated the maximum glycolytic rate in prostate cancer cells. These results were further supported by a reduction in lactate secretion, glucose uptake, and ATP production in sLZIP-knockout prostate cancer cells. sLZIP deficiency hindered cancer growth, as demonstrated by proliferation assays. However, overexpression of PGK1 in sLZIP knockout cells resulted in recovery of aerobic glycolysis. Results of the xenograft experiment revealed that mice injected with sLZIP knockout cells exhibited a decrease in tumor mass compared to those injected with control cells. CONCLUSION: These findings suggest that sLZIP contributes to the metabolic reprogramming of prostate cancer cells via the transcriptional regulation of PGK1.