SUMO and the robustness of cancer

Post-translational protein modification by small ubiquitin-like modifier (SUMO), termed sumoylation, is an important mechanism in cellular responses to stress and one that appears to be upregulated in many cancers. Here, we examine the role of sumoylation in tumorigenesis as a possibly necessary safeguard that protects the stability and functionality of otherwise easily misregulated gene expression programmes and signalling pathways of cancer cells.

[1]  P. Fraser,et al.  Heterologous SUMO-2/3-Ubiquitin Chains Optimize IκBα Degradation and NF-κB Activity , 2012, PloS one.

[2]  Shirin Bonni,et al.  Suppression of TGFβ-Induced Epithelial-Mesenchymal Transition Like Phenotype by a PIAS1 Regulated Sumoylation Pathway in NMuMG Epithelial Cells , 2010, PloS one.

[3]  H. Shih,et al.  Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response , 2013, The EMBO journal.

[4]  Melanie Keppler,et al.  The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress , 2009, Nature.

[5]  T. Ørntoft,et al.  Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts , 2010, BMC Cancer.

[6]  J. Massagué,et al.  Cancer Metastasis: Building a Framework , 2006, Cell.

[7]  Liming Wang,et al.  Differential PIAS3 expression in human malignancy. , 2004, Oncology reports.

[8]  A. Carr,et al.  The Schizosaccharomyces pombe hus5 gene encodes a ubiquitin conjugating enzyme required for normal mitosis. , 1995, Journal of cell science.

[9]  Claus Scheidereit,et al.  A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation. , 2009, Molecular cell.

[10]  M. Lavin,et al.  ATM Activation by Oxidative Stress , 2010, Science.

[11]  Mingyao Liu,et al.  Induction of SENP1 in Endothelial Cells Contributes to Hypoxia-driven VEGF Expression and Angiogenesis* , 2010, The Journal of Biological Chemistry.

[12]  S. Pangas,et al.  Regulation of germ cell function by SUMOylation , 2015, Cell and Tissue Research.

[13]  F. Melchior,et al.  Sumoylation: a regulatory protein modification in health and disease. , 2013, Annual review of biochemistry.

[14]  J. Pouysségur,et al.  HIF1α est une nouvelle cible du facteur de transcription MITF : Implication de la cascade AMPc-MITF-HIF1α dans le développement des melanomas , 2006 .

[15]  T. Sternsdorf,et al.  Evidence for Covalent Modification of the Nuclear Dot–associated Proteins PML and Sp100 by PIC1/SUMO-1 , 1997, The Journal of cell biology.

[16]  H. Saitoh,et al.  Functional Heterogeneity of Small Ubiquitin-related Protein Modifiers SUMO-1 versus SUMO-2/3* , 2000, The Journal of Biological Chemistry.

[17]  R. M. Simpson,et al.  Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9 , 2015, Proceedings of the National Academy of Sciences.

[18]  J. Henley,et al.  SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia , 2013, The EMBO journal.

[19]  K. Brown,et al.  A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma , 2011, Nature.

[20]  K. Bille,et al.  Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). , 2011, Genes & development.

[21]  Tharan Srikumar,et al.  Global analysis of SUMO chain function reveals multiple roles in chromatin regulation , 2013, The Journal of cell biology.

[22]  Shwu‐Yuan Wu,et al.  Crosstalk between sumoylation and acetylation regulates p53‐dependent chromatin transcription and DNA binding , 2009, The EMBO journal.

[23]  S. Manenti,et al.  The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. , 2014, Cell reports.

[24]  O. Jänne,et al.  The Nuclear Receptor Interaction Domain of GRIP1 Is Modulated by Covalent Attachment of SUMO-1* , 2002, The Journal of Biological Chemistry.

[25]  M. Leonard,et al.  Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Shuai,et al.  The Ligase PIAS1 Restricts Natural Regulatory T Cell Differentiation by Epigenetic Repression , 2010, Science.

[27]  Ying Wang,et al.  Redox sensing by proteins: oxidative modifications on cysteines and the consequent events. , 2012, Antioxidants & redox signaling.

[28]  J. Ji,et al.  High-level SAE2 promotes malignant phenotype and predicts outcome in gastric cancer. , 2015, American journal of cancer research.

[29]  R. Rosell,et al.  mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer. , 2011, Journal of the National Cancer Institute.

[30]  Hee June Choi,et al.  Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis , 2006, Nature Cell Biology.

[31]  J. Harper,et al.  TIF1γ Protein Regulates Epithelial-Mesenchymal Transition by Operating as a Small Ubiquitin-like Modifier (SUMO) E3 Ligase for the Transcriptional Regulator SnoN1* , 2014, The Journal of Biological Chemistry.

[32]  Jiaoti Huang,et al.  Overexpression of SKI Oncoprotein Leads to p53 Degradation through Regulation of MDM2 Protein Sumoylation* , 2012, The Journal of Biological Chemistry.

[33]  A. Dejean,et al.  C-terminal modifications regulate MDM2 dissociation and nuclear export of p53 , 2007, Nature Cell Biology.

[34]  Judith Campisi,et al.  Senescent cells as a source of inflammatory factors for tumor progression , 2010, Cancer and Metastasis Reviews.

[35]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[36]  I. Treilleux,et al.  TIF1&ggr; requires sumoylation to exert its repressive activity on TGF&bgr; signaling , 2013, Journal of Cell Science.

[37]  K. M. Taylor,et al.  SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation. , 2005, Developmental cell.

[38]  E. Yeh,et al.  NF-κB induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress. , 2011, Molecular cell.

[39]  W. Paschen,et al.  Small ubiquitin‐like modifier 1–3 is activated in human astrocytic brain tumors and is required for glioblastoma cell survival , 2013, Cancer science.

[40]  N. Ellis,et al.  BLM SUMOylation regulates ssDNA accumulation at stalled replication forks , 2013, Front. Genet..

[41]  M. Einarson,et al.  Human factors and pathways essential for mediating epigenetic gene silencing , 2014, Epigenetics.

[42]  M. Karin,et al.  Immunity, Inflammation, and Cancer , 2010, Cell.

[43]  F. Z. Watts,et al.  Characterisation of Schizosaccharomyces pombe rad31, a UBA-related gene required for DNA damage tolerance. , 1997, Nucleic acids research.

[44]  John V Heymach,et al.  The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. , 2012, Cancer research.

[45]  L. Looijenga,et al.  Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25). , 2005, Human molecular genetics.

[46]  Y. Nakamura,et al.  NF-κB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage , 2007, Oncogene.

[47]  A. Vertegaal,et al.  A comprehensive compilation of SUMO proteomics , 2016, Nature Reviews Molecular Cell Biology.

[48]  Cellular senescence and cancer , 1999, The Journal of pathology.

[49]  J. Manley,et al.  SUMO functions in constitutive transcription and during activation of inducible genes in yeast. , 2010, Genes & development.

[50]  S. Jackson,et al.  RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. , 2012, Genes & development.

[51]  Fang-Rong Hsu,et al.  An improved ChIP-seq peak detection system for simultaneously identifying post-translational modified transcription factors by combinatorial fusion, using SUMOylation as an example , 2014, BMC Genomics.

[52]  S. Dupont,et al.  Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. , 2011, Molecular cell.

[53]  Yuval Hart,et al.  The utility of paradoxical components in biological circuits. , 2013, Molecular cell.

[54]  Jenny G. Parvani,et al.  The relevance of the TGF-β Paradox to EMT-MET programs. , 2013, Cancer letters.

[55]  Yolanda T. Chong,et al.  A Novel Mechanism for SUMO System Control: Regulated Ulp1 Nucleolar Sequestration , 2010, Molecular and Cellular Biology.

[56]  Kam Y. J. Zhang,et al.  Spectomycin B1 as a novel SUMOylation inhibitor that directly binds to SUMO E2. , 2013, ACS chemical biology.

[57]  R. González-Prieto,et al.  c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4 , 2015, Cell cycle.

[58]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[59]  M. Mann,et al.  Ubc9 sumoylation regulates SUMO target discrimination. , 2008, Molecular cell.

[60]  Tetsuya Yamamoto,et al.  Regulation of Transforming Growth Factor-β Signaling by Protein Inhibitor of Activated STAT, PIASy through Smad3* , 2003, Journal of Biological Chemistry.

[61]  G. Semenza Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. , 2012, Trends in pharmacological sciences.

[62]  Ming You,et al.  Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  I. Roninson,et al.  Repression of the SUMO‐specific protease Senp1 induces p53‐dependent premature senescence in normal human fibroblasts , 2008, Aging cell.

[64]  D. Ye,et al.  Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation , 2013, Oncology reports.

[65]  J. Błasiak,et al.  Efficacy of DNA double-strand breaks repair in breast cancer is decreased in carriers of the variant allele of the UBC9 gene c.73G>A polymorphism. , 2010, Mutation research.

[66]  Per Stehmeier,et al.  Regulation of p53 family members by the ubiquitin-like SUMO system. , 2009, DNA repair.

[67]  G. Blobel,et al.  A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex , 1996, The Journal of cell biology.

[68]  Kam Y. J. Zhang,et al.  Advances in the development of SUMO specific protease (SENP) inhibitors , 2015, Computational and structural biotechnology journal.

[69]  D. Jukic,et al.  Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. , 2010, Human pathology.

[70]  M. Boutros,et al.  Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNAi screen. , 2008, Molecular cell.

[71]  S. Müller,et al.  Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor , 2005, Oncogene.

[72]  U. Hamann,et al.  Estrogen Receptor Alpha and Nuclear Factor Y Coordinately Regulate the Transcription of the SUMO-Conjugating UBC9 Gene in MCF-7 Breast Cancer Cells , 2013, PloS one.

[73]  Ji Luo,et al.  A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis , 2012, Science.

[74]  S. Miyamoto,et al.  Sequential Modification of NEMO/IKKγ by SUMO-1 and Ubiquitin Mediates NF-κB Activation by Genotoxic Stress , 2003, Cell.

[75]  Yueqing Bai,et al.  SUMO-specific protease 1 regulates pancreatic cancer cell proliferation and invasion by targeting MMP-9 , 2014, Tumor Biology.

[76]  B. Majello,et al.  SUMO-activating SAE1 transcription is positively regulated by Myc. , 2012, American journal of cancer research.

[77]  Hua Jiang,et al.  β-catenin SUMOylation is involved in the dysregulated proliferation of myeloma cells. , 2015, American journal of cancer research.

[78]  R. DeVita,et al.  Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure , 2015, Nature Communications.

[79]  Darjus F. Tschaharganeh,et al.  Non-Cell-Autonomous Tumor Suppression by p53 , 2013, Cell.

[80]  Xiaozhong Peng,et al.  microRNA-214-mediated UBC9 expression in glioma , 2012, BMB reports.

[81]  Wei Chen,et al.  Negative Regulation of TLR Inflammatory Signaling by the SUMO-deconjugating Enzyme SENP6 , 2013, PLoS pathogens.

[82]  Shelly C. Lu,et al.  S‐adenosyl methionine regulates ubiquitin‐conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers , 2012, Hepatology.

[83]  P. Bork,et al.  Evolution and functional cross‐talk of protein post‐translational modifications , 2013, Molecular systems biology.

[84]  S. Miyamoto,et al.  PIASy mediates NEMO sumoylation and NF-κB activation in response to genotoxic stress , 2006, Nature Cell Biology.

[85]  I. Amit,et al.  Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing , 2015, Nature Immunology.

[86]  George Rajna Link Between Cancer and Aging , 2018 .

[87]  J. Piette,et al.  Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells. , 1996, Nucleic acids research.

[88]  A. Dejean,et al.  The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. , 2006, Molecular cell.

[89]  S. Jentsch,et al.  Protein Group Modification and Synergy in the SUMO Pathway as Exemplified in DNA Repair , 2012, Cell.

[90]  Ruihua Shi,et al.  Over-Expression of Small Ubiquitin-Related Modifier-1 and Sumoylated p53 in Colon Cancer , 2013, Cell Biochemistry and Biophysics.

[91]  B. Liu,et al.  Proinflammatory Stimuli Induce IKKα-Mediated Phosphorylation of PIAS1 to Restrict Inflammation and Immunity , 2007, Cell.

[92]  F. Holsboer,et al.  RSUME, a Small RWD-Containing Protein, Enhances SUMO Conjugation and Stabilizes HIF-1α during Hypoxia , 2007, Cell.

[93]  G. Barton,et al.  Proteotoxic stress reprograms the chromatin landscape of SUMO modification , 2015, Science Signaling.

[94]  Morag Park,et al.  Pc2-mediated Sumoylation of Smad-interacting Protein 1 Attenuates Transcriptional Repression of E-cadherin* , 2005, Journal of Biological Chemistry.

[95]  E. Robertson,et al.  Ubiquitin/SUMO Modification Regulates VHL Protein Stability and Nucleocytoplasmic Localization , 2010, PloS one.

[96]  Xiaoyang Wang,et al.  Increase of SUMO‐1 expression in response to hypoxia: direct interaction with HIF‐1α in adult mouse brain and heart in vivo , 2004, FEBS letters.

[97]  S. Miyamoto,et al.  DNA damage‐dependent NF‐κB activation: NEMO turns nuclear signaling inside out , 2012, Immunological reviews.

[98]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[99]  A. Dejean,et al.  Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance , 2004, The EMBO journal.

[100]  K. Shuai,et al.  Regulation of gene-activation pathways by PIAS proteins in the immune system , 2005, Nature Reviews Immunology.

[101]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[102]  F. Z. Watts Starting and stopping SUMOylation , 2013, Chromosoma.

[103]  F. Melchior,et al.  A Small Ubiquitin-Related Polypeptide Involved in Targeting RanGAP1 to Nuclear Pore Complex Protein RanBP2 , 1997, Cell.

[104]  G. Gill,et al.  Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity. , 2003, Current opinion in genetics & development.

[105]  Pascal Reynier,et al.  Two-step differential expression analysis reveals a new set of genes involved in thyroid oncocytic tumors. , 2005, The Journal of clinical endocrinology and metabolism.

[106]  F. Klein,et al.  Ubc9 sumoylation controls SUMO chain formation and meiotic synapsis in Saccharomyces cerevisiae. , 2013, Molecular cell.

[107]  Z. Yun,et al.  SENP1 regulates cell migration and invasion in neuroblastoma , 2016, Biotechnology and applied biochemistry.

[108]  Chu-Tse Wu,et al.  SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling. , 2015, Biochemical and biophysical research communications.

[109]  J. Henley,et al.  Wrestling with stress: Roles of protein SUMOylation and deSUMOylation in cell stress response , 2014, IUBMB life.

[110]  S. Puig,et al.  A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma , 2011, Nature.

[111]  A. Dejean,et al.  Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation , 2013, Genome research.

[112]  Christopher M Hickey,et al.  Function and regulation of SUMO proteases , 2012, Nature Reviews Molecular Cell Biology.

[113]  E. Yeh,et al.  SENP3-mediated De-conjugation of SUMO2/3 from Promyelocytic Leukemia Is Correlated with Accelerated Cell Proliferation under Mild Oxidative Stress* , 2010, The Journal of Biological Chemistry.

[114]  M. Lei,et al.  Arsenic degrades PML or PML–RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway , 2008, Nature Cell Biology.

[115]  E. Vivés,et al.  SUMOylation of the inducible (c-Fos:c-Jun)/AP-1 transcription complex occurs on target promoters to limit transcriptional activation , 2014, Oncogene.

[116]  J. Olsen,et al.  SUMO-2 Orchestrates Chromatin Modifiers in Response to DNA Damage. , 2015, Cell reports.

[117]  T. Noda,et al.  A metastatic signature in entire lung adenocarcinomas irrespective of morphological heterogeneity. , 2007, Human pathology.

[118]  G. Superti-Furga,et al.  NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation , 2014, Oncogene.

[119]  Peer Bork,et al.  Deciphering a global network of functionally associated post-translational modifications , 2012, Molecular systems biology.

[120]  H. Brauch,et al.  Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade , 2009, International journal of cancer.

[121]  Qin Chen,et al.  De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells , 2014, Oncotarget.

[122]  Sol Efroni,et al.  SENP5 mediates breast cancer invasion via a TGFβRI SUMOylation cascade , 2014, Oncotarget.

[123]  H. Klocker,et al.  PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. , 2012, The American journal of pathology.

[124]  B. Liu,et al.  Control of specificity and magnitude of NF-κB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation , 2007, Proceedings of the National Academy of Sciences.

[125]  M. Khaled,et al.  Hypoxia-inducible factor 1α is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells , 2005, The Journal of cell biology.

[126]  P. B. Chock,et al.  Expression of SUMO-2/3 Induced Senescence through p53- and pRB-mediated Pathways* , 2006, Journal of Biological Chemistry.

[127]  Merlin Crossley,et al.  Modification with SUMO , 2003, EMBO reports.

[128]  M. Tatham,et al.  RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation , 2008, Nature Cell Biology.

[129]  Jaulang Hwang,et al.  Phosphorylation of Ubc9 by Cdk1 Enhances SUMOylation Activity , 2012, PloS one.

[130]  Jennifer S. Yu,et al.  Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress , 2013, Science.

[131]  G. Sethi,et al.  Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. , 2010, Biochimica et biophysica acta.

[132]  Yi-han Shen,et al.  Overexpression of SENP5 in oral squamous cell carcinoma and its association with differentiation. , 2008, Oncology reports.

[133]  M. Teitell,et al.  Negative Regulation of NF-κB Signaling by PIAS1 , 2005, Molecular and Cellular Biology.

[134]  Aline V. Probst,et al.  SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin , 2011, Nature Genetics.

[135]  P. Johnston,et al.  Molecular mechanisms of drug resistance , 2005, The Journal of pathology.

[136]  Yong Xu,et al.  Knockdown of SUMO-activating enzyme subunit 2 (SAE2) suppresses cancer malignancy and enhances chemotherapy sensitivity in small cell lung cancer , 2015, Journal of Hematology & Oncology.

[137]  Xin-Hua Feng,et al.  SUMO-1/Ubc9 Promotes Nuclear Accumulation and Metabolic Stability of Tumor Suppressor Smad4* , 2003, Journal of Biological Chemistry.

[138]  Divya Subramonian,et al.  SUMOylation in Control of Accurate Chromosome Segregation during Mitosis , 2012, Current protein & peptide science.

[139]  Marieke H. Peuscher,et al.  Posttranslational control of telomere maintenance and the telomere damage response , 2012, Cell cycle.

[140]  A. Shen,et al.  PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells , 2013, Journal of Cell Science.

[141]  J. Rao,et al.  PIAS1 Regulates Breast Tumorigenesis through Selective Epigenetic Gene Silencing , 2014, PloS one.

[142]  A. Dejean,et al.  Conjugation with the ubiquitin‐related modifier SUMO‐1 regulates the partitioning of PML within the nucleus , 1998, The EMBO journal.

[143]  R. Chanet,et al.  A New Saccharomyces cerevisiae Strain with a Mutant Smt3-Deconjugating Ulp1 Protein Is Affected in DNA Replication and Requires Srs2 and Homologous Recombination for Its Viability , 2004, Molecular and Cellular Biology.

[144]  S. Kogan,et al.  A sumoylation site in PML/RARA is essential for leukemic transformation. , 2005, Cancer cell.

[145]  Samantha G. L. Keyser,et al.  An electrophoretic mobility shift assay identifies a mechanistically unique inhibitor of protein sumoylation. , 2013, Chemistry & biology.

[146]  Jian Zhang,et al.  SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane , 2012, Nature Communications.

[147]  Xin Yu,et al.  Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer. , 2002, The American journal of pathology.

[148]  E. J. Lee,et al.  SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination , 2006, Nature Cell Biology.

[149]  H. Tagawa,et al.  Molecular cytogenetic analysis of the breakpoint region at 6q21–22 in T‐cell lymphoma/leukemia cell lines , 2002, Genes, chromosomes & cancer.

[150]  R. Hay,et al.  SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. , 1998, Molecular cell.

[151]  G. Barton,et al.  System-Wide Changes to SUMO Modifications in Response to Heat Shock , 2009, Science Signaling.

[152]  J. Iñiguez-Lluhí,et al.  The in Vivo Role of Androgen Receptor SUMOylation as Revealed by Androgen Insensitivity Syndrome and Prostate Cancer Mutations Targeting the Proline/Glycine Residues of Synergy Control Motifs* , 2012, The Journal of Biological Chemistry.

[153]  Jinke Cheng,et al.  Induction of the SUMO-specific Protease 1 Transcription by the Androgen Receptor in Prostate Cancer Cells* , 2007, Journal of Biological Chemistry.

[154]  Jinke Cheng,et al.  SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia , 2007, Cell.

[155]  Terry D. Lee,et al.  Small Ubiquitin-like Modifier (SUMO) Modification of E1 Cys Domain Inhibits E1 Cys Domain Enzymatic Activity* , 2012, The Journal of Biological Chemistry.

[156]  H. de Thé,et al.  Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication , 2014, Nature Communications.

[157]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[158]  Ville Paakinaho,et al.  Global SUMOylation on active chromatin is an acute heat stress response restricting transcription , 2015, Genome Biology.

[159]  K. Ohta,et al.  Ubc9- and Mms21-Mediated Sumoylation Counteracts Recombinogenic Events at Damaged Replication Forks , 2006, Cell.

[160]  Kai Wu,et al.  RETRACTED ARTICLE: SUMO-specific protease 6 promotes gastric cancer cell growth via deSUMOylation of FoxM1 , 2015, Tumor Biology.

[161]  J. Campisi,et al.  Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[162]  E. Yeh,et al.  Differential expression of SUMO-specific protease 7 variants regulates epithelial–mesenchymal transition , 2012, Proceedings of the National Academy of Sciences.

[163]  D. Durocher,et al.  Regulation of DNA damage responses by ubiquitin and SUMO. , 2013, Molecular cell.

[164]  E. Yeh,et al.  SENP3 is responsible for HIF‐1 transactivation under mild oxidative stress via p300 de‐SUMOylation , 2009, The EMBO journal.

[165]  S. Jackson,et al.  Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks , 2009, Nature.

[166]  M. Kelliher,et al.  A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage , 2011, Molecular and Cellular Biology.

[167]  J. Campisi,et al.  Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts , 2012, Cancer Microenvironment.

[168]  M. Kulesz-Martin,et al.  NF-κB Repression by PIAS3 Mediated RelA SUMOylation , 2012, PloS one.

[169]  Bart Barlogie,et al.  The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. , 2010, Blood.

[170]  Shuomin Zhu,et al.  MicroRNA-mediated Regulation of Ubc9 Expression in Cancer Cells , 2009, Clinical Cancer Research.

[171]  Edward T H Yeh,et al.  SUMO Losing Balance: SUMO Proteases Disrupt SUMO Homeostasis to Facilitate Cancer Development and Progression. , 2010, Genes & cancer.

[172]  K. Georgopoulos,et al.  Ikaros SUMOylation: Switching Out of Repression , 2005, Molecular and Cellular Biology.

[173]  R. Weichselbaum,et al.  Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. , 1991, The Journal of clinical investigation.

[174]  V. Beneš,et al.  SUMOylation regulates the chromatin occupancy and anti-proliferative gene programs of glucocorticoid receptor , 2013, Nucleic acids research.

[175]  E. Robertson,et al.  Hypoxia Inactivates the VHL Tumor Suppressor through PIASy-Mediated SUMO Modification , 2010, PloS one.

[176]  M. Matunis,et al.  SUMO: a multifaceted modifier of chromatin structure and function. , 2013, Developmental cell.

[177]  N. Dantuma,et al.  Spatiotemporal regulation of posttranslational modifications in the DNA damage response , 2016, The EMBO journal.

[178]  F. Melchior,et al.  Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. , 2006, Molecular cell.

[179]  H. Kato,et al.  PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells , 2013, British Journal of Cancer.

[180]  Pei-Chih Lee,et al.  SUMOylated SoxE factors recruit Grg4 and function as transcriptional repressors in the neural crest , 2012, The Journal of cell biology.

[181]  J. Campisi Aging, cellular senescence, and cancer. , 2013, Annual review of physiology.

[182]  M. Schmitz,et al.  SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death. , 2010, Molecular cell.

[183]  Kun Huang,et al.  Chromatin modification by SUMO-1 stimulates the promoters of translation machinery genes , 2012, Nucleic acids research.

[184]  A. Vertegaal,et al.  SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer. , 2015, Trends in biochemical sciences.

[185]  Yu Fan,et al.  SUMO-Specific Protease 2 Suppresses Cell Migration and Invasion through Inhibiting the Expression of MMP13 in Bladder Cancer Cells , 2013, Cellular Physiology and Biochemistry.

[186]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[187]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[188]  R. Derynck,et al.  The type I TGF-β receptor is covalently modified and regulated by sumoylation , 2008, Nature Cell Biology.

[189]  C. Grou,et al.  Heat shock induces a massive but differential inactivation of SUMO-specific proteases. , 2012, Biochimica et biophysica acta.

[190]  Minoru Yoshida,et al.  Kerriamycin B inhibits protein SUMOylation , 2009, The Journal of Antibiotics.

[191]  J. Piette,et al.  Importance of PIKKs in NF-κB activation by genotoxic stress. , 2011, Biochemical pharmacology.

[192]  J. McNally,et al.  Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. , 2004, Nucleic acids research.

[193]  M. Fallahi,et al.  Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. , 2014, Blood.

[194]  Xin Lu,et al.  SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence , 2011, Cell Death and Differentiation.

[195]  Denglong Wu,et al.  Prognostic impact of SUMO-specific protease 1 (SENP1) in prostate cancer patients undergoing radical prostatectomy. , 2013, Urologic oncology.

[196]  Minoru Yoshida,et al.  Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. , 2009, Chemistry & biology.

[197]  J. Olson,et al.  SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression , 2014, Nature Communications.

[198]  C. Gong,et al.  Ubc9 expression predicts chemoresistance in breast cancer , 2011, Chinese journal of cancer.

[199]  C. Schmidt,et al.  At the crossroads of SUMO and NF-κB , 2003, Molecular Cancer.

[200]  R. Derynck,et al.  Sumoylation of Smad4, the Common Smad Mediator of Transforming Growth Factor-β Family Signaling* , 2003, Journal of Biological Chemistry.

[201]  D. Jukic,et al.  SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas , 2007, Oncogene.

[202]  Brian D. Bennett,et al.  A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2 , 2016, Stem cell reports.

[203]  H. Brauch,et al.  Polymorphisms in the UBC9 and PIAS3 genes of the SUMO-conjugating system and breast cancer risk , 2010, Breast Cancer Research and Treatment.

[204]  R. Kanaar,et al.  Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage , 2013, Journal of Cell Science.

[205]  H. Shih,et al.  Daxx Mediates the Small Ubiquitin-like Modifier-dependent Transcriptional Repression of Smad4* , 2005, Journal of Biological Chemistry.

[206]  Jie Li,et al.  Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. , 2014, Cancer cell.

[207]  D. Coppola,et al.  Substantially reduced expression of PIAS1 is associated with colon cancer development , 2009, Journal of Cancer Research and Clinical Oncology.

[208]  A. Sapetschnig,et al.  SUMO‐modified Sp3 represses transcription by provoking local heterochromatic gene silencing , 2008, EMBO reports.

[209]  Mel Campbell,et al.  The chromatin modification by SUMO-2/3 but not SUMO-1 prevents the epigenetic activation of key immune-related genes during Kaposi’s sarcoma associated herpesvirus reactivation , 2013, BMC Genomics.

[210]  G. Collins The next generation. , 2006, Scientific American.

[211]  P. Pandolfi,et al.  Role of SUMO-1-modified PML in nuclear body formation. , 2000, Blood.

[212]  W. Pavan,et al.  Frequent mutations in the MITF pathway in melanoma , 2009, Pigment cell & melanoma research.