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HIF2α Promotes Cancer Metastasis through TCF7L2-Dependent Fatty Acid Synthesis in ccRCC

Authors :
Jian Shi
Qingyang Lv
Daojia Miao
Zhiyong Xiong
Zhihao Wei
Songming Wu
Diaoyi Tan
Keshan Wang
Xiaoping Zhang
Source :
Research, Vol 7 (2024)
Publication Year :
2024
Publisher :
American Association for the Advancement of Science (AAAS), 2024.

Abstract

Recent studies have highlighted the notable involvement of the crosstalk between hypoxia-inducible factor 2 alpha (HIF2α) and Wnt signaling components in tumorigenesis. However, the cellular function and precise regulatory mechanisms of HIF2α and Wnt signaling interactions in clear cell renal cell carcinoma (ccRCC) remain elusive. To analyze the correlation between HIF2α and Wnt signaling, we utilized the Cancer Genome Atlas - Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) public database, HIF2α RNA sequencing data, and conducted luciferase reporter assays. A Wnt-related gene set was employed to identify key regulators of Wnt signaling controlled by HIF2α in ccRCC. Furthermore, we assessed the biological effects of TCF7L2 on ccRCC metastasis and lipid metabolism in both in vivo and in vitro settings. Our outcomes confirm TCF7L2 as a key gene involved in HIF2α-mediated regulation of the canonical Wnt pathway. Functional studies demonstrate that TCF7L2 promotes metastasis in ccRCC. Mechanistic investigations reveal that HIF2α stabilizes TCF7L2 mRNA in a method based on m6A by transcriptionally regulating METTL3. Up-regulation of TCF7L2 enhances cellular fatty acid oxidation, which promotes histone acetylation. This facilitates the transcription of genes connected to epithelial–mesenchymal transition and ultimately enhances metastasis of ccRCC. These outcomes offer a novel understanding into the involvement of lipid metabolism in the signaling pathway regulation, offering valuable implications for targeted treatment in ccRCC.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
26395274
Volume :
7
Database :
Directory of Open Access Journals
Journal :
Research
Publication Type :
Academic Journal
Accession number :
edsdoj.0c87a6ed113840ebac0bc18c6c733636
Document Type :
article
Full Text :
https://doi.org/10.34133/research.0322