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      The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

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          Abstract

          Ferroptosis, a novel form of regulated cell death, is different from other types of cell death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on cell death linked to cardiomyopathy, tumorigenesis, and cerebral hemorrhage to name a few. Here we summarize current literature on ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming and epigenetic regulators in cancer progression. With regard to organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction and golgi stress-related lipid peroxidation all contribute to induction of ferroptosis. Understanding the underlying mechanism in ferroptosis could provide insight into the treatment of various intractable diseases including cancers.

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          ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

          Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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            Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

            Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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              Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

              Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial–mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
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                Author and article information

                Contributors
                xdsh96@21cn.com
                shuangliu2016@csu.edu.cn
                taoyong@csu.edu.cn
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                27 February 2020
                27 February 2020
                2020
                : 19
                : 39
                Affiliations
                [1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, , Central South University, ; Changsha, 410078 Hunan China
                [2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, , Central South University, ; Changsha, 410078 Hunan China
                [3 ]GRID grid.410356.5, ISNI 0000 0004 1936 8331, Department of Biomedical and Molecular Sciences, , Queen’s University, ; Kingston, Ontario Canada
                [4 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, , Central South University, ; Changsha, 410008 Hunan China
                [5 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, , Central South University, ; Changsha, 410011 China
                Author information
                http://orcid.org/0000-0003-2354-5321
                Article
                1157
                10.1186/s12943-020-01157-x
                7045519
                32103754
                66a8f12a-428d-43c4-ac06-a256c46d4392
                © The Author(s) 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 October 2019
                : 13 February 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81874139
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012166, National Basic Research Program of China (973 Program);
                Award ID: 2015CB553903
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                ferroptosis,epigenetics,cancer,organelles,chromatin remodeling factor,lncrna,golgi,lysosome,endoplasmic reticulum,mitochondria,metabolism,iron,lipid peroxidation,immunotherapy

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