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Small ubiquitin-like modifier 1-3 conjugation [corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival.

ABSTRACT: Small ubiquitin-like modifier (SUMO1-3) constitutes a group of proteins that conjugate to lysine residues of target proteins thereby modifying their activity, stability, and subcellular localization. A large number of SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression. Furthermore, SUMO conjugation plays key roles in genome stability, quality control of newly synthesized proteins, proteasomal degradation of proteins, and DNA damage repair. Any marked increase in levels of SUMO-conjugated proteins is therefore expected to have a major impact on the fate of cells. We show here that SUMO conjugation is activated in human astrocytic brain tumors. Levels of both SUMO1- and SUMO2/3-conjugated proteins were markedly increased in tumor samples. The effect was least pronounced in low-grade astrocytoma (WHO Grade II) and most pronounced in glioblastoma multiforme (WHO Grade IV). We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. Blocking SUMO1-3 conjugation in glioblastoma cells by silencing their expression blocked DNA synthesis, cell growth, and clonogenic survival of cells. It also resulted in DNA-dependent protein kinase-induced phosphorylation of H2AX, indicative of DNA double-strand damage, and G(2) /M cell cycle arrest. Collectively, these findings highlight the pivotal role of SUMO conjugation in DNA damage repair processes and imply that the SUMO conjugation pathway could be a new target of therapeutic intervention aimed at increasing the sensitivity of glioblastomas to radiotherapy and chemotherapy.

SUBMITTER: Yang W

PROVIDER: S-EPMC3608476 | biostudies-literature |

REPOSITORIES: biostudies-literature

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| S-ECPF-MEXP-567 | biostudies-other

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| S-EPMC8472834 | biostudies-literature

Global Trends in Survival From Astrocytic Tumors in Adolescents and Young Adults: A Systematic Review.

Project description:BackgroundBrain tumors represent an important cause of cancer-related death in adolescents and young adults. Most are diagnosed in low-income and middle-income countries. We aimed to conduct the first, to our knowledge, systematic review of time trends and geographical variation in survival in this age group.MethodsWe included observational studies describing population-based survival from astrocytic tumors in patients aged 15-39 years. We queried 6 electronic databases from database inception to December 31, 2019. This review is registered with PROSPERO, number CRD42018111981.ResultsAmong 5640 retrieved records, 20 studies fulfilled the inclusion criteria. All but 1 study focused on high-income countries. Five-year survival from astrocytoma (broad morphology group) mostly varied between 48.0% and 71.0% (1973-2004) without clear trends or geographic differences. Adolescents with astrocytoma had better outcomes than young adults, but survival values were similar when nonmalignant tumors were excluded. During 2002-2007, 5-year survival for World Health Organization grade I-II tumors was in the range of 72.6%-89.1% in England, Germany, and the United States but lower in Southeastern Europe (59.0%). Five-year survival for anaplastic astrocytoma varied between 39.6% and 55.4% (2002-2007). Five-year survival from glioblastoma was in the range of 14.2%-23.1% (1991-2009).ConclusionsSurvival from astrocytic tumors remained somewhat steady over time, with little change between 1973 and 2009. Survival disparities were difficult to examine, because nearly all the studies were conducted in affluent countries. Studies often adopted the International Classification of Childhood Cancer, which, however, did not allow to accurately describe variation in survival. Larger studies are warranted, including underrepresented populations and providing more recent survival estimates.

| S-EPMC7583144 | biostudies-literature

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