NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation

Licciardello, Marco P.; Müllner, Markus K.; Dürnberger, Gerhard; Kerzendorfer, Claudia; Boidol, Bernd; Trefzer, Claudia; Sdelci, Sara; Berg, Tiina; Penz, Thomas; Schuster, Michael; Bock, Christoph; Královics, Róbert; Superti‐Furga, Giulio; Colinge, Jacques; Nijman, Sebastian M.; Kubicek, Stefan

doi:10.1038/onc.2014.319

Cited by 41 publications

(31 citation statements)

References 55 publications

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“…SENP2 is one of several genes on the amplified region of chromosome 3q with the capacity to influence survival to DNA-damaging therapeutics. Evidence of SUMO-pathway addiction has been found in Myc-and Ras-driven cancers (Kessler et al 2012;Yu et al 2015), while those with low SUMOylation may be sensitive to further targeting of the SUMO system (Licciardello et al 2015). Differential needs for SUMO conjugation and deconjugation therefore could expose tumorspecific vulnerabilities.…”

Section: Discussionmentioning

confidence: 99%

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

et al. 2019

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SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

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Section: Discussionmentioning

confidence: 99%

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

et al. 2019

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“…Recently, an interaction between the Notch1 receptor and the SUMOylation cascade has been described in breast cancer [23]. Small ubiquitin-like modifier (SUMO), a small (11 kDa) ubiquitin-like protein, can covalently attach to proteins as a post-translational modification and influence their stability, localization, or activity [24].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways

Ciria

García

Ontoria‐Oviedo

et al. 2017

Stem Cells and Development

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Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1α) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1α in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1α in MSCs increased protein levels of the Notch ligands Jagged 1–2 and Delta-like (Dll)1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by γ-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1α expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization.

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“…Chemical inhibitors, such as ginkgolic acid and anacardic acid, bind to the SUMO activating enzyme and block the E1-SUMO intermediate [88]. Treatment of NOTCH1-activated breast epithelial cells with ginkgolic acid, for example, reduces cell proliferation and induces apoptosis, suggesting a potential effect of this SUMOylation inhibitor on NOTCH1-driven breast cancer [89]. Reactive oxygen species (ROS) can inhibit both the SUMO activating and SUMO conjugating enzymes in a different manner, via the formation of reversible disulfide bridges between the catalytic cysteine residues [90].…”

Section: Targeting the Sumo Systemmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation

Cited by 41 publications

References 55 publications

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

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