The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis.
Zuli WangLianlian OuyangNa LiuTiansheng LiBokang YanChao MaoDesheng XiaoBoyi GanShuang LiuKonstantin M J SparrerPublished in: Oncogene (2023)
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.
Keyphrases
- cell death
- cell cycle arrest
- cancer stem cells
- induced apoptosis
- stem cells
- epithelial mesenchymal transition
- cancer therapy
- endoplasmic reticulum stress
- drug delivery
- signaling pathway
- oxidative stress
- cell proliferation
- gene expression
- genome wide
- small molecule
- protein protein
- single molecule
- amino acid
- long non coding rna