RAD51 can inhibit PDGF-B–induced gliomagenesis and genomic instability

Westermark, Ulrica; Lindberg, Nanna; Roswall, Pernilla; Bråsäter, Daniel; Helgadottir, Hildur R.; Hede, Sanna-Maria; Zetterberg, Anders; Jasin, Maria; Nistér, Monica; Uhrbom, Lene

doi:10.1093/neuonc/nor131

Cited by 12 publications

(7 citation statements)

References 42 publications

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“…Several studies have demonstrated that activation of DDR-DNA repair system works as an oncogene-induced barrier against tumor establishment (Bartek et al, 2007;Squatrito and Holland, 2011), and mutations or alterations that lead to loss of function or downregulation could represent a trigger for gliomagenesis (Cha and Yim, 2013). In a study using a mouse model for glioma development, it was demonstrated that the induced expression of RAD51, a central protein for repair by homologous recombination (HR), decreases both the incidence of oncogene-induced glioma and the genomic instability, impairing carcinogenesis (Westermark et al, 2011). Using a similar model, Squatrito and colleagues showed that components of the DDR pathway are frequently altered in gliomas and loss of ATM or its downstream targets accelerates tumor formation (Squatrito et al, 2010).…”

Section: Dna Repair Functions In Tumorigenesis and Progressionmentioning

confidence: 99%

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

et al. 2020

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Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, showing rapid development and resistance to therapies. On average, patients survive 14.6 months after diagnosis and less than 5% survive five years or more. Several pieces of evidence have suggested that the DNA damage signaling and repair activities are directly correlated with GBM phenotype and exhibit opposite functions in cancer establishment and progression. The functions of these pathways appear to present a dual role in tumorigenesis and cancer progression. Activation and/or overexpression of ATRX, ATM and RAD51 genes were extensively characterized as barriers for GBM initiation, but paradoxically the exacerbated activity of these genes was further associated with cancer progression to more aggressive stages. Excessive amounts of other DNA repair proteins, namely HJURP, EXO1, NEIL3, BRCA2, and BRIP, have also been connected to proliferative competence, resistance and poor prognosis. This scenario suggests that these networks help tumor cells to manage replicative stress and treatment-induced damage, diminishing genome instability and conferring therapy resistance. Finally, in this review we address promising new drugs and therapeutic approaches with potential to improve patient survival. However, despite all technological advances, the prognosis is still dismal and further research is needed to dissect such complex mechanisms.

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Section: Dna Repair Functions In Tumorigenesis and Progressionmentioning

confidence: 99%

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

et al. 2020

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“…These hyperplasias had activated DNA damage response in terms of 53BP1 foci, phosphorylated histone H2AX and Chk2, increased p53 levels, and apoptosis likely as a result of DNA damage response ( 36 ). PDGF-B over-expression has also been shown to induce DNA damage response, genomic instability and ploidy in glial cells, and hyperplastic lesions of the brain and subsequent gliomas ( 37 ). Over-expression of cyclin E, common in cancer and rapidly cycling cells, results in increases in Ser 15-phosphorylated p53, γ-H2AX, and Ser 966-phosphorylated cohesin SMC1, which are all targets of the DNA damage response kinases ATM and ATR ( 34 ).…”

Section: Prolonged or Abnormal Growth Factor Signalingmentioning

confidence: 99%

PDGF in gliomas: more than just a growth factor?

Lindberg¹,

Holland²

2012

Upsala Journal of Medical Sciences

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Platelet-derived growth factor B (PDGF-B) is a growth factor promoting and regulating cell migration, proliferation, and differentiation, involved in both developmental processes and in maintaining tissue homeostasis under strict regulation. What are the implications of prolonged or uncontrolled growth factor signaling in vivo, and when does a growth factor such as PDGF-B become an oncogene? Under experimental conditions, PDGF-B induces proliferation and causes tumor induction. It is not known whether these tumors are strictly a PDGF-B-driven proliferation of cells or associated with secondary genetic events such as acquired mutations or methylation-mediated gene silencing promoting neoplasia. If PDGF-B-driven tumorigenesis was only cellular proliferation, associated changes in gene expression would thus be correlated with proliferation and not associated with secondary events involved in tumorigenesis and neoplastic transformation such as cycle delay, DNA damage response, and cell death. Changes in gene expression might be expected to be reversible, as is PDGF-B-driven proliferation under normal circumstances. Since PDGF signaling is involved in oligodendrocyte progenitor cell differentiation and maintenance, it is likely that PDGF-B stimulates proliferation of a pool of cells with that phenotype, and inhibition of PDGF-B signaling would result in reduced expression of oligodendrocyte-associated genes. More importantly, inhibition of PDGF signaling would be expected to result in reversion of genes induced by PDGF-B accompanied by a decrease in proliferation. However, if PDGF-B-driven tumorigenesis is more than simply a proliferation of cells, inhibition of PDGF signaling may not reverse gene expression or halt proliferation. These fundamental questions concerning PDGF-B as a potential oncogene have not been resolved.

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“…Accumulated evidence has established critical roles for the tumor suppressor p53-binding protein 1 (53BP1) in non-homologous end-joining (NHEJ) double-stand break (DSB) DNA repair [30–32], and Rad51 in homologous recombination (HR) DSB DNA repair [33]. In addition, 53BP1 and Rad51 are important for glioma tumorigenesis [6, 34]. Based on our results above, we hypothesized that G0S2 enhances radiation resistance of gliomas through regulation of Rad51 or 53BP1.…”

Section: Resultsmentioning

confidence: 99%

Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response

Wang

Hou

Zhang

et al. 2019

J Exp Clin Cancer Res

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Background Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. Methods Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan–Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining. Results Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. Conclusions Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas. Electronic supplementary material The online version of this article (10.1186/s13046-019-1151-x) contains supplementary material, which is available to authorized users.

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RAD51 can inhibit PDGF-B–induced gliomagenesis and genomic instability

Cited by 12 publications

References 42 publications

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

PDGF in gliomas: more than just a growth factor?

Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response

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