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Inactivation of the AMPK–GATA3–ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth

Authors :
Wei Dong Zang
Rui Zhao
Bo Dai
Jian-Yuan Zhao
Shu Xian Zhou
Qian Zhou
Guo Hai Shi
Fu Jiang Xu
Xuan Zhang
Yi Jun Shen
Yuan-Yuan Qu
Wenhao Xu
Hai Liang Zhang
Yao Zhu
Wei Xu
Yan Lin
Yiping Zhu
Kun Chang
Ning Shao
Cheng Tao Han
Dingwei Ye
Shimin Zhao
Source :
Cancer Research. 80:319-333
Publication Year :
2020
Publisher :
American Association for Cancer Research (AACR), 2020.

Abstract

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)–GATA-binding protein 3 (GATA3)–enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK–GATA3–ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. Significance: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK–GATA3–ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Details

ISSN :
15387445 and 00085472
Volume :
80
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi.dedup.....483ab17f7013255ae83ede71f21dc08c