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

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

PROVIDER: PRJNA801613 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17804564.fastq.gz	Fastqsanger.gz
	SRR17804565.fastq.gz	Fastqsanger.gz
	SRR17804566.fastq.gz	Fastqsanger.gz
	SRR17804567.fastq.gz	Fastqsanger.gz
	SRR17804568.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Project description: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.

2022-01-31 | GSE195639 | GEO

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

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

| S-EPMC7612586 | biostudies-literature

The interplay between RNA sequestration in P-bodies and chromatin architecture sustains myeloid leukemia

Project description:The interplay between RNA sequestration in P-bodies and chromatin architecture sustains myeloid leukemia

| PRJNA933139 | ENA

Linalool, an aromatic terpenoid, rewires transcriptome profile of lipid-loaded HepG2 cells

Project description:The microarray results showed that linalool sitimulation of lipid-loaded HepG2 cells rewired the hepatic transcriptome profile, with linalool being comparable to those of fenofibrate. Total of 8,988 genes that were commonly and significantly expressed in all experimental groups, including control hepatocytes, lipid-loaded hepatocytes, and lipid-loaded hepatocyted stimulated with linalool or fenofibrate, respectively, to compare the transcriptome profile of linalool (1mM) with those of hypotriglyceridemic drug, fenofibrate (100 ?M). Lipid loading of hepatocytes notably changed hepatic transcriptome profile, where 77 % of the selected genes showed >20% changes in expression (fold change > 1.2 or fold change <0.8). However, linalool stimulation of lipid-loaded cells showed that 48 % of the selected genes had expression changes of >20%. Thus, 29 % of the selected genes became to show less than 20% changes in expression after linalool stimulation compared to the lipid-loaded condition. Fenofibrate showed 46 % of the selected gene expression changes of >20%. Thus, 31 % of the seleted genes fell into the <20% change category compared to the lipid-loaded condition after fenofibrate stimulation. Untreated control vs. lipid-loaded HepG2 cells (3 biological replicates), untreated control vs. lipid-loaded HepG2 cells treated with fenofibrate (3 biological replicates), untreated control vs. lipid-loaded HepG2 cells treated with linalool (2 biological replicates). One replicate per array

2013-04-11 | E-GEOD-45961 | biostudies-arrayexpress

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

Project description:Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

| PRJNA748429 | ENA

Identification of genes regulated by L-lactate and by DL-lactate in Lactobacillus plantarum

Project description:L. plantarum is known to possess an L-lactate inducible lactate racemase activity (Goffin et al. 2005. J. Bacteriol. 187:6750). In the present study, microarrays were used in order to identify all genes that are up-regulated by L-lactate, but not by a racemic mixture of D- and L-lactate. A mutant of L. plantarum NCIMB8826 deficient for NAD-dependent L-lactate activity (TF101; Ferain et al. 1994. 176:596), and thus producing no L-lactate, was grown in MRS medium at 28Â°C until mid-exponential phase (OD600nm 0.75). The culture was then divided into 3 sub-cultures. Optically pure sodium L-lactate (200 mM) was added to the first sub-culture (TF101 + L-lac 200 mM). An equimolar mixture of sodium D- and L-lactate (100 mM each) was added to the second sub-culture (TF101 + L/D-lac 200 mM). The third sub-culture was not treated (TF101; reference sample). The three sub-cultures were further incubated at 28Â°C for 1h30 (a time known to be sufficient for induction of lactate racemase activity by L-lactate). Cells were harvested by centrifugation. Microarray data were used ot identify genes that are specifically induced by L-lactate (comparison of TF101 with TF101 + L-lac 200 mM), but not by DL-lactate (comparison of TF101 with T101 + L/D-lac 200 mM). There are no biological replicates.

2013-07-01 | E-GEOD-43518 | biostudies-arrayexpress

The interplay between RNA sequestration in P-bodies and chromatin architecture sustains myeloid leukemia [CUT&RUN]

Project description:The interplay between RNA sequestration in P-bodies and chromatin architecture sustains myeloid leukemia [CUT&RUN]

| PRJNA1086193 | ENA

Identification of genes regulated by L-lactate and by DL-lactate in Lactobacillus plantarum

2013-07-01 | GSE43518 | GEO

Lactate sensing drives fungal immune evasion

Project description:Experiment Description RNA sequencing was performed on Candida albicans wild type cells (SC5314) grown to exponential phase on YNB Lactate, YNB Glucose, or YNB Glucose plus Lactate, and compared to exponential Candida albicans crz1 cells grown on YNB Glucose or YNB Glucose plus Lactate. Three independent experiments were performed.

2016-10-03 | E-MTAB-4579 | biostudies-arrayexpress

Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies.

Project description:Microenvironment is known to influence cancer drug response and sustain resistance to therapies targeting receptor-tyrosine kinases. However if and how tumor microenvironment can be altered during treatment, contributing to resistance onset is not known. Here we show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift towards increased glycolysis and lactate production. We identified secreted lactate as the key molecule able to instruct Cancer Associated Fibroblasts (CAFs) to produce Hepatocyte Growth Factor (HGF) in a NF-KB dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional targeting or pharmacological inhibition of lactate dehydrogenase prevented and overcame in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This non-cell-autonomous, adaptive resistance mechanism was observed in NSCLC patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance

2018-07-06 | GSE115172 | GEO

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