A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
复制标题
ZEB2和ACSL4之间存在正反馈回路，调节脂质代谢，促进乳腺癌转移。
作者：
Lin J;Zhang P;Liu W;Liu G;Zhang J;Yan M;Duan Y;Yang N
脂质代谢在癌症转移中起着关键作用。然而，转移基因调节脂质代谢的机制仍不清楚。在这里，我们描述了上皮-间充质转化转录因子ZEB 2和关键脂质酶ACSL 4（长链酰基辅酶A合成酶4）之间的一个新的致癌-代谢反馈回路，导致细胞脂质储存和脂肪酸氧化（FAO）增强，从而驱动乳腺癌转移。在功能上，ZEB 2或ACSL 4的耗竭显著降低了脂滴（LD）丰度和细胞迁移。ACSL 4过表达挽救了ZEB 2敲低细胞的侵袭能力，表明ACSL 4对ZEB 2介导的转移至关重要。从机制上讲，ZEB 2通过直接结合ACSL 4启动子激活ACSL 4表达。ACSL 4通过减少ZEB 2泛素化结合并稳定ZEB 2。值得注意的是，ACSL 4不仅促进细胞内脂肪生成和LD积累，而且还通过上调FAO限速酶CPT 1A（肉毒碱棕榈酰转移酶1亚型A）来增强FAO和三磷酸腺苷的产生。最后，我们证明了ACSL 4敲低显著减少了体内转移性肺淋巴结。总之，我们揭示了ZEB 2和ACSL 4之间的一种新的正调控环，该环促进LD储存以满足乳腺癌转移的能量需求，并将ZEB 2-ACSL 4信号传导轴确定为克服乳腺癌转移的有吸引力的治疗靶点。
Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic–metabolic feedback loop between the epithelial–mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2–ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.