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Broadening horizons: the role of ferroptosis in cancer. Chen Xin,Kang Rui,Kroemer Guido,Tang Daolin Nature reviews. Clinical oncology The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy. 10.1038/s41571-020-00462-0
Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53. EMBO reports Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non-apoptotic cell death characterized by the iron-dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin-induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis. 10.15252/embr.201847563
The role of ubiquitination in hepcidin-independent and hepcidin-dependent degradation of ferroportin. Cell metabolism The iron exporter ferroportin (Fpn) is essential to transfer iron from cells to plasma. Systemic iron homeostasis in vertebrates is regulated by the hepcidin-mediated internalization of Fpn. Here, we demonstrate a second route for Fpn internalization; when cytosolic iron levels are low, Fpn is internalized in a hepcidin-independent manner dependent upon the E3 ubiquitin ligase Nedd4-2 and the Nedd4-2 binding protein Nfdip-1. Retention of cell-surface Fpn through reductions in Nedd4-2 results in cell death through depletion of cytosolic iron. Nedd4-2 is also required for internalization of Fpn in the absence of ferroxidase activity as well as for the entry of hepcidin-induced Fpn into the multivesicular body. C. elegans lacks hepcidin genes, and C. elegans Fpn expressed in mammalian cells is not internalized by hepcidin but is internalized in response to iron deprivation in a Nedd4-2-dependent manner, supporting the hypothesis that Nedd4-2-induced internalization of Fpn is evolutionarily conserved. 10.1016/j.cmet.2011.09.008
Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4. Zhang Wen,Jiang Baoping,Liu Yunxin,Xu Li,Wan Meng Free radical biology & medicine Ferroptosis is a new form of regulated cell death that is dependent on iron- and lipid reactive oxygen species. Emerging evidence indicate that induction of ferroptosis could inhibit the proliferation of diverse cancer cells, which functions as a potent tumor suppressor in cancer. Here, we firstly reported Bufotalin (BT), a natural small molecule, was a novel glutathione peroxidase 4 (GPX4) inhibitor, which could trigger the ferroptosis in non-small cell lung cancer cells. In vitro, BT significantly inhibited the proliferation of A549 cells and induced the ferroptosis, whereas ferroptosis inhibitor or iron chelator significantly reversed the cytotoxicity of BT on A549 cells. Moreover, BT also increased the intracellular Fe. Subsequently, immunoblotting showed that BT could inhibit the protein expression of GPX4. Notably, BT dramatically accelerated the degradation of GPX4 in A549 cells. Immunoprecipitation assay further certified the increased ubiquitination of GPX4 induced by BT. Nevertheless, BT could not further increase the lipid ROS after silencing of GPX4, suggesting the induction of ferroptosis by BT was dependent on GPX4. Furthermore, BT also observably inhibited tumor growth and promoted lipid peroxidation in vivo. In conclusion, our findings indicated that BT could induce ferroptosis and cause lipid peroxidation by accelerating the degradation of GPX4 and raising the intracellular Fe, and BT will hopefully serve as a lead compound in developing anti-tumor agents for targeting ferroptosis. 10.1016/j.freeradbiomed.2022.01.009