Zeb1-mediated control of the PUFA/MUFA ratio in EMT-associated ferroptosis sensitivity

铁凋亡是一种高度保守的细胞死亡途径，依赖于铁和氧自由基介导的磷脂过氧化。重要的是，这样的磷脂需要由某些种类的多不饱和脂肪酸（PUFA）组成。与细胞凋亡（分化细胞（例如上皮细胞）中的主要死亡途径）相反，铁凋亡可以主要在未分化细胞和具有（部分）间充质表型的细胞中进行。在癌细胞中，这种表型通常通过上皮-间质转化（EMT）程序的激活而获得，并且与高转移能力和治疗抗性相关。我们可以证明EMT激活转录因子Zeb 1强烈增加PUFA水平，而它减少了抵消单不饱和脂肪酸（MUFA）。我们将证明Zeb 1是否直接调节PUFA与MUFA合成的限速酶的表达，即下调硬脂酰辅酶A去饱和酶1（SCD 1）的表达，这对MUFA合成至关重要，并上调脂肪酸去饱和酶2（FADS 2）的表达和极长链脂肪酸5（VL 5）的延伸，这两种酶都是PUFA合成的限速酶。我们将进一步证明，如果改变这些酶的表达和功能的帐户与（部分）间充质表型的癌细胞中的Zeb 1相关的铁凋亡敏感性。最后，我们将测试其表达和功能的特定调节剂是否支持铁凋亡激活作为针对高度侵袭性癌症类型的治疗策略。

Ferroptosis is a highly conserved cell death pathway, depending on an iron and oxygen-radical mediated peroxidation of phospholipids. Importantly, such phospholipids need to be composed of certain species of polyunsaturated fatty acids (PUFAs). In contrast to apoptosis, the prominent death pathway in differentiated cells (e.g. epithelial cells), ferroptosis can be executed predominantly in undifferentiated cells and cells with a (partial) mesenchymal phenotype. In cancer cells this phenotype is often acquired by activation of the epithelial-mesenchymal transition (EMT) program, and associated with high metastatic competence and therapy-resistance. We could demonstrate that the EMT-activating transcription factor Zeb1 strongly increases PUFA-levels, whereas it decreases the counteracting monounsaturated fatty acids (MUFAs). We will proof if Zeb1 directly regulates the expression of the rate-limiting enzymes for PUFA- vs. MUFA-synthesis, i.e. downregulates expression of stearyl Co-A desaturase 1 (SCD1), which is critical for MUFA synthesis, and upregulates expression of fatty acid desaturase 2 (FADS2) and elongation of very long chain fatty acid 5 (ELOVL5), both rate-limiting enzymes for PUFA synthesis. We will further proof if altered expression and function of these enzymes accounts for the Zeb1-associated ferroptosis sensitivity in cancer cells with a (partial) mesenchymal phenotype. Finally, we will test if specific modulators of their expression and function will support ferroptosis activation as therapeutic strategy against highly aggressive cancer types.