跳轉至內容
Merck
  • Lactate Rewires Lipid Metabolism and Sustains a Metabolic-Epigenetic Axis in Prostate Cancer.

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

Cancer research (2022-02-10)
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
摘要

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. This work shows that stromal-derived lactate induces accumulation of lipid droplets, stimulates epigenetic rewiring, and fosters metastatic potential in prostate cancer.

材料
產品編號
品牌
產品描述

Sigma-Aldrich
嘌呤霉素 二盐酸盐 来源于白色链球菌, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Anti-PLIN2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution