Lactate rewires lipid metabolism and sustains a metabolic-epigenetic interplay in prostate cancer

Lactate is abundant in the tumor environment as the secreted product of fermentative cells. In prostate cancer (PCa), cancer-associated fibroblasts are the major contributors and this secreted lactate is uptaken by cancer cells to sustain their mitochondrial metabolism. However, how lactate controls the metabolic and transcriptional regulation in tumors is far to be elucidated. Here, we identify an innovative lactate-driven mechanism able to increase the expression of genes involved in lipid metabolism in PCa cells. This regulation enhances intracellular lipid accumulation in lipid droplets (LDs) and provides acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic control. Interestingly, inhibition of this loop by targeting bromodomains histone acetylation readers suppresses the expression of perilipin-2 (PLIN2), a crucial component of LDs, disrupting the lactate-dependent lipid metabolic rewiring. Since this metabolic-epigenetic regulatory loop sustains PCa metastatic potential, its targeting is of clinical relevance as demonstrated by the inhibition of PCa invasive potential in vivo. Overall, our findings show that lactate has both a metabolic and an epigenetic role in promoting PCa progression. Overall design: RNA-seq analysis of 16 samples: 4 DU145 control cells; 4 DU145 treated with Lactate; 4 DU145 treated with I-BET762; 4 DU145 trated with Lactate and I-BET762