Lactate Rewires Lipid Metabolism and Sustains a Metabolic–Epigenetic Axis in Prostate Cancer

Abstract

Lactate is an abundant oncometabolite in the tumor environment. In prostate cancer, cancer-associated fibroblasts (CAF) are major contributors of secreted lactate, which can be taken up by cancer cells to sustain mitochondrial metabolism. However, how lactate impacts transcriptional regulation in tumors has yet to be fully elucidated. Here, we describe a mechanism by which CAF-secreted lactate is able to increase the expression of genes involved in lipid metabolism in prostate cancer cells. This regulation enhanced intracellular lipid accumulation in lipid droplets (LD) and provided acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic modification. Inhibition of this loop by targeting the bromodomain and extraterminal protein family of histone acetylation readers suppressed the expression of perilipin 2 (PLIN2), a crucial component of LDs, disrupting lactate-dependent lipid metabolic rewiring. Inhibition of this CAF-induced metabolic–epigenetic regulatory loop in vivo reduced growth and metastasis of prostate cancer cells, demonstrating its translational relevance as a therapeutic target in prostate cancer. Clinically, PLIN2 expression was elevated in tumors with a higher Gleason grade and in castration-resistant prostate cancer compared with primary prostate cancer. Overall, these findings show that lactate has both a metabolic and an epigenetic role in promoting prostate cancer progression. Significance: This work shows that stromal-derived lactate induces accumulation of lipid droplets, stimulates epigenetic rewiring, and fosters metastatic potential in prostate cancer.

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

“…They showed differences in metabolic processes, metabolic signaling, DNA repair, and mitosis. These different processes and signals were involved in immune responses [ 27 , 28 , 29 ], which meant the lactate groups may be related with immunotherapy and survival. As shown in Figure 5 A, the high and low score were bridge-connected immune subtypes [ 30 , 31 ] and patient survival.…”

The importance of being CAFs (in cancer resistance to targeted therapies)

“…CAFs also contribute to the generation and maintenance of the cancer stem cell ‘niche’ through the active remodeling of ECM and secretion of morphogens [ 7 , 8 ]. CAFs regulate ferroptosis in surrounding tumor cells [ 9 ] and they also develop metabolic symbiosis with cancer cells, mutually and dynamically reprogramming their basal metabolism- comprising lipid metabolism [ 10 , 11 ] - in surrounding tumor cells to generate a pro-tumorigenic ecosystem [ 12 ]. CAFs do not only interact with tumor cells, but they are functionally connected also with other cells in the tumor microenvironment, including vascular endothelial cells and immune cells.…”

Emerging Roles of Lipophagy in Cancer Metastasis

“…In response to an increase in cellular FAs levels, LD biogenesis is stimulated. Of note, acidic microenvironment caused by tumors favors the synthesis and release of LDs [ 101 , 102 ]. LDs vary in size and number in different cell types, revealing the capacity of managing lipid storage [ 103 ].…”