DUBA-SLC7A11-c-Myc轴对干细胞性质和铁死亡至关重要。
The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis.
发表日期：2023 Aug 03
作者：
Zuli Wang, Lianlian Ouyang, Na Liu, Tiansheng Li, Bokang Yan, Chao Mao, Desheng Xiao, Boyi Gan, Shuang Liu, Yongguang Tao
来源：
Stem Cell Research & Therapy
摘要：
铁死亡（Ferroptosis）具有独特的铁依赖性细胞死亡特点，其特点是脂质过氧化的积累。然而，干细胞（stemness）与铁死亡之间的相互作用尚不清楚。本研究表明，与分化细胞相比，未分化细胞对铁死亡更为敏感，而半胱氨酸转运蛋白SLC7A11在分化细胞中由去泛素酶DUBA高度上调。此外，DUBA通过去泛素化SLC7A11促进干细胞状态。此外，SLC7A11通过半胱氨酸显著增加c-Myc的表达，索拉非尼和c-Myc抑制剂EN4的联合应用对癌症治疗具有协同作用。综上，我们的研究结果揭示了增强的干细胞状态会增加对铁死亡的敏感性，而DUBA-SLC7A11-c-Myc轴对铁死亡具有抵抗力的分化癌干细胞（CSCs）至关重要，为通过铁死亡消灭CSCs提供了有前景的靶点。© 2023年。作者在Springer Nature Limited独家许可下发表。
Ferroptosis is characterized by the accumulation of lipid peroxidation as a unique iron-dependent cell death. However, the interplay between stemness and ferroptosis remains unknown. Here, we demonstrate that undifferentiated cells are more sensitive to ferroptosis than differentiated cells, and cystine transporter SLC7A11 protein is highly up-regulated by deubiquitinase DUBA in differentiated cells. Additionally, DUBA promotes stemness by deubiquitinating SLC7A11. Moreover, SLC7A11 drastically increases the expression of c-Myc through cysteine, the combination of sorafenib and c-Myc inhibitor EN4 has a synergetic effect on cancer therapy. Together, our results reveal that enhanced stemness increases the susceptibility to ferroptosis, and the DUBA-SLC7A11-c-Myc axis is pivotal for differentiated cancer stem cells (CSCs) resistant to ferroptosis, providing a promised targets to eradicate CSCs through ferroptosis.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.