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

• DOI: 10.1158/0008-5472.c.6513861.v1
• Publication Date: 2023-03-31T21:18:05Z
• Authors: Luigi Ippolito; Giuseppina Comito; Matteo Parri; Marta Iozzo; Assia Duatti; Francesca Virgilio; Nicla Lorito; Marina Bacci; Elisa Pardella; Giada Sandrini; Francesca Bianchini; Roberta Damiano; Lavinia Ferrone; Giancarlo la Marca; Sergio Serni; Pietro Spatafora; Carlo V. Catapano; Andrea Morandi; Elisa Giannoni; Paola Chiarugi
• Keywords: Lipid droplet

<div>Abstract<p>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 tumors has yet fully elucidated. Here, we describe a mechanism CAF-secreted able increase expression genes involved lipid metabolism cells. This enhanced intracellular accumulation droplets (LD) and provided acetyl moieties for histone acetylation, establishing regulatory loop between metabolites epigenetic modification. Inhibition this targeting bromodomain extraterminal protein family acetylation readers suppressed perilipin 2 (PLIN2), crucial component LDs, disrupting lactate-dependent metabolic rewiring. CAF-induced metabolic–epigenetic <i>in vivo</i> reduced growth metastasis cells, demonstrating its translational relevance as therapeutic target cancer. Clinically, PLIN2 was elevated with higher Gleason grade castration-resistant compared primary Overall, these findings show that both role promoting progression.</p>Significance:<p>This work shows stromal-derived induces droplets, stimulates rewiring, fosters metastatic potential cancer.</p></div>