An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability

Nagy, Zsuzsanna; Seneviratne, Janith A.; Kanikevich, Maxwell; Chang, William K.; Mayoh, Chelsea; Venkat, Pooja; Du, Yanhua; Jiang, Cizhong; Salib, Alice; Koach, Jessica; Carter, Daniel; Mittra, Rituparna; Liu, Tao; Parker, Michael W.; Cheung, Belamy B.; Marshall, Glenn M.

doi:10.1038/s41467-021-22143-x

Cited by 39 publications

(34 citation statements)

References 72 publications

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“…The known role of ALYREF as a regulator of DNA binding guided further analyses that uncovered ALYREF-MYCN interaction in a nuclear coactivator complex which stimulates transcription of the 'ubiquitin specific peptidase 3 (USP3), consequently reducing MYCN ubiquitination and degradation. This finding therefore opens novel opportunities for targeting this deubiquitinase activity through the development of USP3 inhibitors [68].…”

Section: Alyrefmentioning

confidence: 89%

“…The Marshall team used a bioinformatic approach to identify critical genes on 17q in high-risk NBs by evaluating frequency of gains distal to 17q21.31 using whole genome sequencing data from NB tumors from the US TARGET database [68]. A total of 1044 transcripts from the 17q21-ter locus were analyzed for differential gene expression in 17q21-tergain patients (1) and MYCN-amplified patients (2) in the same cohort.…”

Section: Alyrefmentioning

confidence: 99%

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From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

Decaesteker

Durinck

Roy

et al. 2021

JPM

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Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.

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Section: Alyrefmentioning

confidence: 89%

Section: Alyrefmentioning

confidence: 99%

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

Decaesteker

Durinck

Roy

et al. 2021

JPM

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“…We further explored the detailed interactions and regulatory mechanisms between USP3 and COL9A3 or COL6A5. As a DUB, USP3 has been identified to have deubiquitination effects on its wide targets within cellular entities and during cell activities in various malignancies [ 10 , 11 , 27 , 28 ]. Das et al have shown that USP3 can upregulate the expression of Cdc25A through its DUB activity, which promotes cell cycle progression and tumorigenesis [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation

Wang

Zhu³

et al. 2021

Cell Death Dis

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As an important regulator of intracellular protein degradation, the mechanism of the deubiquitinating enzyme family in tumour metastasis has received increasing attention. Our previous study revealed that USP3 promotes tumour progression and is highly expressed in gastric cancer (GC). Herein, we report two critical targets, COL9A3 and COL6A5, downstream of USP3, via the isobaric tags for relative and absolute quantification technique. Mechanistically, we observed that USP3 interacted with and stabilised COL9A3 and COL6A5 via deubiquitination in GC. Importantly, we found that COL9A3 and COL6A5 were essential mediators of USP3-modulated oncogenic activity in vitro and in vivo. Examination of clinical samples confirmed that elevated expression of USP3, concomitant with increased COL9A3 and COL6A5 abundance, correlates with human GC progression. These data suggest that USP3 promotes GC progression and metastasis by deubiquitinating COL9A3 and COL6A5. These findings identify a mechanism of GC metastasis regarding USP3-mediated deubiquitinating enzyme activity and suggest potential therapeutic targets for GC management.

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“…Increased NME1 gene expression has also been associated with high-risk NB, suggesting a potential role of histidine kinase signalling in tumour pathogenesis [ 25 ]. Moreover, ALYREF gene has been proposed as a codriver factor for oncogenesis in NB by in vitro and in vivo transgenic models, co-operating with N-Myc for USP3 transcription upregulation, and thus regulating MYCN turnover [ 26 ]. However, a better definition of these genes’ involvement is still to be determined.…”

Section: Genetic Predisposition and Chromosome Instability In Nbmentioning

confidence: 99%

Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs

Ciaccio

Rosa

Aloisi

et al. 2021

IJMS

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Neuroblastoma (NB) is one of the most frequently occurring neurogenic extracranial solid cancers in childhood and infancy. Over the years, many pieces of evidence suggested that NB development is controlled by gene expression dysregulation. These unleashed programs that outline NB cancer cells make them highly dependent on specific tuning of gene expression, which can act co-operatively to define the differentiation state, cell identity, and specialized functions. The peculiar regulation is mainly caused by genetic and epigenetic alterations, resulting in the dependency on a small set of key master transcriptional regulators as the convergence point of multiple signalling pathways. In this review, we provide a comprehensive blueprint of transcriptional regulation bearing NB initiation and progression, unveiling the complexity of novel oncogenic and tumour suppressive regulatory networks of this pathology. Furthermore, we underline the significance of multi-target therapies against these hallmarks, showing how novel approaches, together with chemotherapy, surgery, or radiotherapy, can have substantial antineoplastic effects, disrupting a wide variety of tumorigenic pathways through combinations of different treatments.

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An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability

Cited by 39 publications

References 72 publications

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation

Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs

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