PO.MCB02.01 · 分子与细胞生物学
靶向组蛋白乙酰转移酶GCN5使癌细胞对铁死亡敏感
Targeting the histone acetyltransferase GCN5 sensitizes cancer cells to ferroptosis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
铁死亡是一种铁依赖性的调节性细胞死亡形式，在癌症中的意义日益凸显。然而，其完整的调控网络，尤其是表观遗传调控，仍知之甚少。在此，我们鉴定出组蛋白乙酰转移酶GCN5是铁死亡的一个关键新型介导因子。我们证明，铁死亡诱导剂Erastin和RSL3以GCN5依赖的方式触发活性氧（ROS）产生、脂质过氧化以及不稳定铁的累积。GCN5的基因敲低或药理抑制可改善Erastin/RSL3诱导的线粒体功能障碍（包括ROS、脂质过氧化和动力学受损），恢复内质网（ER）稳态，并使自噬流恢复正常。此外，Erastin/RSL3以GCN5依赖的方式上调了若干转录因子。值得注意的是，HDAC抑制剂诱导的细胞死亡在Erastin或RSL3作用下得到协同增强，提示了一种颇具前景的联合治疗策略。总之，我们的研究确立了GCN5作为铁死亡的核心调控因子，通过线粒体、自噬和核内通路调控铁死亡的执行。这些发现提名GCN5作为使癌症对铁死亡敏感的治疗靶点。
查看英文原文 English abstract
Ferroptosis is an iron-dependent form of regulated cell death with emerging significance in cancer. However, its full regulatory network, particularly epigenetic regulation, remains poorly understood. Here, we identify the histone acetyltransferase GCN5 as a critical novel mediator of ferroptosis. We demonstrate that the ferroptosis inducers Erastin and RSL3 trigger reactive oxygen species (ROS) production, lipid peroxidation, and labile iron accumulation in a GCN5-dependent manner. Genetic knockdown or pharmacological inhibition of GCN5 ameliorated Erastin/RSL3-induced mitochondrial dysfunction (including ROS, lipid peroxidation, and impaired dynamics), restored endoplasmic reticulum (ER) homeostasis, and normalized autophagic flux. Furthermore, Erastin/RSL3 upregulated several transcription factors in a GCN5-dependent manner. Notably, HDAC inhibitor-induced cell death was synergistically enhanced by Erastin or RSL3, suggesting a compelling combination therapy strategy.In conclusion, our work establishes GCN5 as a central regulator of ferroptosis, governing its execution through mitochondrial, autophagic, and nuclear pathways. These findings nominate GCN5 as a therapeutic target to sensitize cancers to ferroptosis.
利益披露 Disclosure
L. Chang, None..
S. Chiang, None..
S. Chen, None.