MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma

King, David S.; Li, Xiao Dun; Almeida, Gilberto S.; Kwok, Colin; Gravells, Polly; Harrison, Daniel; Burke, S.V.; Hallsworth, Albert; Jamin, Yann; George, Sally L.; Robinson, Simon P.; Lord, Christopher J.; Poon, Evon; Yeomanson, Daniel; Chesler, Louis; Bryant, Helen E.

doi:10.18632/oncotarget.27329

Cited by 22 publications

(28 citation statements)

References 55 publications

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“…Among the key cellular processes governed by MYCN , cell death is a puzzling phenomenon. On one hand, it is the cause of tumor growth under nutrient-deprived conditions whose adaptation promotes NB progression 7 , 8 ; on other hand, abnormal expression of MYCN leads to the direct activation of cell death pathways 9 , 10 . This contradiction indicates that MYCN finely regulates the balance between cell survival and cell death.…”

Section: Introductionmentioning

confidence: 99%

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

Yang

et al. 2021

Cell Death Dis

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MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

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Section: Introductionmentioning

confidence: 99%

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

Yang

et al. 2021

Cell Death Dis

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“…Hence, it is not clear how many patients identified in this study will in fact have HRD or would benefit from PARP inhibition. Additionally, clinical response to PARP inhibition is not solely driven by HRD, involving several other factors including replication, oxidative, and ER stress [65][66][67][68][69] . www.nature.com/scientificreports/ www.nature.com/scientificreports/ Therefore, specific alterations to these and other genes warrant further investigation prior to any being proposed as a reliable surrogate for HRD, particularly in the setting of other cellular processes.…”

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confidence: 99%

Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Principe

Narbutis

Koch

et al. 2020

Sci Rep

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PARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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“…1e), another gene located in chromosome region 11q. Inhibition of PARP1 [39,40] and PCNA [41] have previously been investigated in NB, while FEN1 is known to be up regulated in tumors with MYCN ampli cation [42]. To further investigate these ndings, we silenced the y orthologue gene dmDLG in a Drosophila model, which subsequently resulted in increased dmFEN and dmPARP, thereby reproducing the altered PARP1 andFEN1 expression found in NB patient samples and NB cell lines (Fig.…”

Section: Discussionmentioning

confidence: 96%

DLG2 Impairs dsDNA Break Repair and Maintains Genome Integrity in Neuroblastoma

Keane

Weerd

Ejeskär

2021

Preprint

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Background: In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. Microhomology mediated-end joining (MMEJ) is an error-prone pathway for DNA double-strand break repair that is often upregulated in cancer. DLG2, a candidate tumor suppressor gene on chromosome 11q, has previously been implicated in DNA repair.Methods: We evaluated an association between MMEJ gene expression and neuroblastoma patient outcome, risk categorization, and 11q status using publicly available microarray data from independent neuroblastoma patient datasets. Functional studies were conducted using comet assay and H2AX phosphorylation in neuroblastoma cell lines and in the fruit fly with UVC-induced DNA breaks. Results: We show that the MMEJ genes PARP1 and FEN1 are over expressed in neuroblastoma and restoration of DLG2 impairs their gene and protein expression. When exposed to UVC radiation, cells with DLG2 over expression show less DNA fragmentation and induce apoptosis in a p53 S46 dependent manner. We could also confirm that DLG2 expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance. Conclusions: Taken together, we show that DLG2 expression increases p53 mediated apoptosis in response to genotoxicity, by maintaining S317 CHK1 phosphorylation and reducing the DNA replication machinery.

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MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma

Cited by 22 publications

References 55 publications

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

DLG2 Impairs dsDNA Break Repair and Maintains Genome Integrity in Neuroblastoma

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