Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression.
J Exp Clin Cancer Res
; 41(1): 28, 2022 Jan 19.
Article
en En
| MEDLINE
| ID: mdl-35045880
ABSTRACT
BACKGROUND:
Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study.METHODS:
TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids.RESULTS:
TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (181/226) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (181/182) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (181/182) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis.CONCLUSION:
Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (181/226) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (181/182) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Endometriales
/
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice
/
Fluidez de la Membrana
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
J Exp Clin Cancer Res
Año:
2022
Tipo del documento:
Article
País de afiliación:
China