Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth
Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth
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AMPK-GATA3-ECHS1 通路失活可诱导脂肪酸合成，促进透明细胞肾细胞癌生长
DOI：
10.1158/0008-5472.can-19-1023
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发表时间：
2020-01-15
期刊：
影响因子：
11.2
通讯作者：
Zhao, Jian-Yuan
中科院分区：
文献类型：
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作者：
Qu, Yuan-Yuan;Zhao, Rui;Zhao, Jian-Yuan
通常在许多癌症中观察到的脂质积累的致瘤作用和潜在机制仍然没有得到充分的理解。在这项研究中，我们确定了一个AMP激活的蛋白激酶（AMPK）-GATA结合蛋白3（GATA 3）-烯酰辅酶A水合酶短链1（ECHS 1）途径，该途径可诱导透明细胞肾细胞癌（ccRCC）中的脂质积聚并促进细胞增殖。ECHS 1的表达降低，负责脂肪酸（FA）氧化的失活和从头FA合成的激活，与ccRCC进展呈正相关，并预测患者生存率差。从机制上讲，ECHS 1下调诱导FA和支链氨基酸（BCAA）的积累，这抑制了AMPK促进的GATA 3（ECHS 1的转录激活因子）的表达。BCAA积累诱导mTORC 1激活和FA重新合成，并促进细胞增殖。此外，GATA 3表达在预测ccRCC进展和患者生存方面表现为模仿ECHS 1。AMPK-GATA 3-ECHS 1通路可能为临床提供新的治疗方法和预后评估。意义：这些发现揭示了ccRCC中脂质积聚的分子机制，提示AMPK-GATA 3-ECHS 1通路可能是潜在的治疗靶点和预后生物标志物。
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.