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

Jian Shi; Qingyang Lv; Daojia Miao; Zhiyong Xiong; Zhihao Wei; Songming Wu; Diaoyi Tan; Keshan Wang; Xiaoping Zhang

doi:10.34133/research.0322

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

Research (Wash D C). 2024 Feb 22:7:0322. doi: 10.34133/research.0322. eCollection 2024.

Authors

Jian Shi^{1

2}, Qingyang Lv^{1

2}, Daojia Miao^{1

2}, Zhiyong Xiong^{1

2}, Zhihao Wei^{1

2}, Songming Wu^{1

2}, Diaoyi Tan^{1

2}, Keshan Wang^{1

2}, Xiaoping Zhang^{1

2}

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, P. R. China.
² Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, P. R. China.

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.