Abstract
BackgroundEstrogen-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.MethodsTFEB 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.ResultsTFEB 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.ConclusionLipid 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.
Highlights
Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression
PG (18:1/22:6) + H induced by transcription factor EB (TFEB)-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis
Bioinformatics analysis revealed that TFEB promotes ERRα transcription to participate in EC progression To explore the role of TFEB and ERRα in EC, we first investigated the expression and clinicopathological data of these two genes in 543 EC samples and 23 normal samples from the Cancer Genome Atlas (TCGA) RNA-seq database
Summary
Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. 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. High body mass index (BMI) influences the current and future health of patients and is considered one of the top 5 global causes of death for females [1]. Endometrial cancer (EC) is most strongly associated with obesity, and obesity has been considered a very important risk factor for EC in postmenopausal women [2]. The age-standardized incidence of EC was 63.4 per 100,000, the mortality rate was 21.8 per 100,000, and the 5-year relative survival was 72.8% from 2012–2015 [4]. The mechanism of lipid metabolism in EC is still unclear
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