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      BAP1 links metabolic regulation of ferroptosis to tumor suppression


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          The roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in cancer remain unclear. The tumor suppressor BRCA1-associated protein 1 ( BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin. Here integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, and identify cystine transporter SLC7A11 as a key BAP1 target gene in human cancers. Functional studies reveal that BAP1 decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression in a DUB-dependent manner and that BAP1 inhibits cystine uptake through repressing SLC7A11 expression, leading to elevated lipid peroxidation and ferroptosis. Furthermore, we show that BAP1 inhibits tumor development partly through SLC7A11 and ferroptosis and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, our results uncover a previously unappreciated epigenetic mechanism coupling ferroptosis to tumor suppression.

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          Most cited references40

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Ferroptosis: process and function.

            Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.
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              Role of histone H2A ubiquitination in Polycomb silencing.

              Covalent modification of histones is important in regulating chromatin dynamics and transcription. One example of such modification is ubiquitination, which mainly occurs on histones H2A and H2B. Although recent studies have uncovered the enzymes involved in histone H2B ubiquitination and a 'cross-talk' between H2B ubiquitination and histone methylation, the responsible enzymes and the functions of H2A ubiquitination are unknown. Here we report the purification and functional characterization of an E3 ubiquitin ligase complex that is specific for histone H2A. The complex, termed hPRC1L (human Polycomb repressive complex 1-like), is composed of several Polycomb-group proteins including Ring1, Ring2, Bmi1 and HPH2. hPRC1L monoubiquitinates nucleosomal histone H2A at lysine 119. Reducing the expression of Ring2 results in a dramatic decrease in the level of ubiquitinated H2A in HeLa cells. Chromatin immunoprecipitation analysis demonstrated colocalization of dRing with ubiquitinated H2A at the PRE and promoter regions of the Drosophila Ubx gene in wing imaginal discs. Removal of dRing in SL2 tissue culture cells by RNA interference resulted in loss of H2A ubiquitination concomitant with derepression of Ubx. Thus, our studies identify the H2A ubiquitin ligase, and link H2A ubiquitination to Polycomb silencing.

                Author and article information

                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1 August 2018
                10 September 2018
                October 2018
                10 March 2019
                : 20
                : 10
                : 1181-1192
                [1 ]Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
                [2 ]Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
                [3 ]Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
                [4 ]Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.
                [5 ]The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, 6767 Bertner Ave., Houston, Texas 77030, USA.
                [6 ]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
                [7 ]Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
                [8 ]Present address: Institute of Biology, Westlake University, Hangzhou, Zhejiang Province, 310024, P. R. China.
                [9 ]Present address: Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, P. R. China.
                [10 ]These authors contributed equally to this work.
                Author notes
                [* ]Corresponding Authors: Boyi Gan. bgan@ 123456mdanderson.org ; Phone: 713-792-8653; Fax: 713-794-5369. Wei Li. WL1@ 123456bcm.edu ; Phone: 713-798-7854; Fax: 713-798-2716.

                Author Contributions

                Y.Z. performed most of the experiments shown in Figures 37 with assistance from X.Liu, P.K., K.S., H.L., L.Z., and Z.X.; J.S. conducted all the computational analyses shown in Figures 12. F.L. and G.C. helped with cystine uptake experiments. W.Y. helped with the 4HNE IHC analysis. Z.G. conducted tandem affinity purification to identify BAP1-associated proteins. X.Li analyzed BAP1-associated proteins. B.G. and W.L. supervised the study. Y.Z. and B.G. designed the experiments and wrote the manuscript. J.C., M.H. and P.H. helped with discussion and interpretation of results. All authors commented on the manuscript.


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                Cell biology
                bap1,h2a ubiquitination,ferroptosis,metabolic stress,slc7a11,tumor suppression
                Cell biology
                bap1, h2a ubiquitination, ferroptosis, metabolic stress, slc7a11, tumor suppression


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