Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation.
Acetylation
/ drug effects
Animals
Biological Transport
/ drug effects
Cadherins
/ metabolism
Carcinoma, Renal Cell
/ genetics
Cell Line, Tumor
Cell Movement
/ drug effects
Chickens
Coumaric Acids
/ pharmacology
Culture Media, Conditioned
/ pharmacology
Down-Regulation
/ drug effects
Epigenesis, Genetic
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
Histones
/ metabolism
Humans
Kidney
/ drug effects
Kidney Neoplasms
/ genetics
Lactic Acid
/ pharmacology
Monocarboxylic Acid Transporters
/ metabolism
Neoplasm Invasiveness
Niacinamide
/ pharmacology
Signal Transduction
/ drug effects
Sirtuin 1
/ metabolism
Smad4 Protein
/ metabolism
Warburg effect
epigenetic regulation
lactate
renal cell carcinoma
sirtuin 1
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
23 04 2020
23 04 2020
Historique:
received:
30
03
2020
revised:
16
04
2020
accepted:
18
04
2020
entrez:
29
4
2020
pubmed:
29
4
2020
medline:
20
2
2021
Statut:
epublish
Résumé
Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms' regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate's impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.
Sections du résumé
BACKGROUND
Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms' regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate's impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC.
METHODS
In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues.
RESULTS
Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues.
CONCLUSIONS
In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.
Identifiants
pubmed: 32340156
pii: cells9041053
doi: 10.3390/cells9041053
pmc: PMC7226526
pii:
doi:
Substances chimiques
Cadherins
0
Coumaric Acids
0
Culture Media, Conditioned
0
Histones
0
Monocarboxylic Acid Transporters
0
Smad4 Protein
0
Niacinamide
25X51I8RD4
alpha-cyano-4-hydroxycinnamate
28166-41-8
Lactic Acid
33X04XA5AT
Sirtuin 1
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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