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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2022

Open Access 01-12-2022 | Endometrial Cancer | Research

Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression

Authors: Xiaodan Mao, Huifang Lei, Tianjin Yi, Pingping Su, Shuting Tang, Yao Tong, Binhua Dong, Guanyu Ruan, Alexander Mustea, Jalid Sehouli, Pengming Sun

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2022

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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) (18:1/22:6) + 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 (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + 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 (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.
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Metadata
Title
Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression
Authors
Xiaodan Mao
Huifang Lei
Tianjin Yi
Pingping Su
Shuting Tang
Yao Tong
Binhua Dong
Guanyu Ruan
Alexander Mustea
Jalid Sehouli
Pengming Sun
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2022
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02211-2

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