LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer.

ABSTRACT: Neuroendocrine prostate cancer (NEPC) evolves as an aggressive phenotype during prolonged androgen deprivation therapy, lacking effective clinical management. In this study, we elucidated a reciprocal metabolic-epigenetic mechanism involving a positive feedback loop between glycolysis and the transcription factor LHX2 that promotes prostate cancer progression. Mechanistically, enzalutamide-mediated inhibition of the androgen receptor led to upregulation of key glycolytic enzymes. Elevated glycolysis resulted in lactate accumulation and subsequent histone lactylation, which in turn enhanced LHX2 expression. Reciprocally, LHX2 transcriptionally activated the lactate dehydrogenase LDHA, which further amplified lactate production. Furthermore, LHX2 augmented the expression of the lineage-deter

SUBMITTER: Jiang J 

PROVIDER: S-EPMC12666319 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature