1. Inactivation of the AMPK–GATA3–ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth
- Author
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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, and Shimin Zhao
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,mTORC1 ,AMP-Activated Protein Kinases ,Kidney ,Nephrectomy ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,ECHS1 ,Enoyl-CoA Hydratase ,Aged, 80 and over ,Mice, Knockout ,Chemistry ,Fatty Acids ,Middle Aged ,Prognosis ,Kidney Neoplasms ,Progression-Free Survival ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Adult ,Down-Regulation ,GATA3 Transcription Factor ,Mechanistic Target of Rapamycin Complex 1 ,Young Adult ,03 medical and health sciences ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein kinase A ,Carcinoma, Renal Cell ,Fatty acid synthesis ,Aged ,Cell Proliferation ,Cell growth ,Lipogenesis ,AMPK ,medicine.disease ,Clear cell renal cell carcinoma ,HEK293 Cells ,030104 developmental biology ,Cancer research ,Amino Acids, Branched-Chain - 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.
- Published
- 2020