A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at the<i>TRKA</i>and<i>p75NTR</i>Promoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGF

Iraci, Nunzio; Diolaiti, Daniel; Papa, Antonella; Porro, Antônio; Valli, Emanuele; Gherardi, Samuele; Herold, Steffi; Eilers, Martin; Bernardoni, Roberto; Valle, Giuliano Della; Perini, Giovanni

doi:10.1158/0008-5472.can-10-2627

Cited by 87 publications

(90 citation statements)

References 36 publications

(46 reference statements)

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“…38), and MYC oncogenes can directly regulate promoter methylation (39,40) and increase HDAC expression (41). It has recently been shown that MYCN binding as a SP1/MIZ1/MYCN complex recruits HDAC1 to local histones as well (42). Our data suggests that some of these repressive effects may be critically regulated by the extent of MYCN promoter occupancy, distinguishing MYCN function in amplified and nonamplified neuroblastoma.…”

Section: Discussionmentioning

confidence: 61%

A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma

Shohet

Ghosh²,

Coarfa³

et al. 2011

Cancer Research

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MYCN is a major driver of neuroblastoma tumorigenesis and MYCN amplification is the worst prognostic indicator of aggressive NB. To identify potentially therapeutic tumor suppressor microRNAs for aggressive NB, we utilized a conditional MYCN system to simulate MYCN-amplified and nonamplified tumor types and performed a genome-wide search for MYCN target microRNA promoters differentially repressed under high MYCN conditions. We identified 20 gene promoters hosting 30 microRNAs that were directly bound and differentially regulated by MYCN. Eleven of these genes showed significant clinical correlations for neuroblastoma with 4 genes linked with better survival and 7 genes linked with poor survival. Surprisingly, expression analysis of host genes and microRNAs demonstrated that 8 of 11 pairs were repressed by high levels of MYCN regardless of the clinical correlation of the host gene. We therefore predicted these intronic microRNAs would be tumor suppressors. In fact, detailed gain of function studies for two miRs, miR-591 and miR-558, confirmed potent tumor suppressive effects for miR-591 in orthotopic neuroblastoma xenografts. However, miR-558 markedly increased colony formation, proliferation, and tumor growth in vivo. Our data reveal host-gene independent functions of MYCN-target microRNAs and demonstrate that MYCN represses both tumor suppressive and proproliferative microRNAs. Cancer Res; 71(11); 3841-51. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 61%

A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma

Shohet

Ghosh²,

Coarfa³

et al. 2011

Cancer Research

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“…No significant enrichment was observed among down-regulated genes; thus, down-regulation of MYCN-157 genes occurs mainly via alternative ways. Several mechanisms have been described, including interference with transcription factors MIZ1 and Sp1 (12,13) and induction of microRNA expression (14,15).…”

Section: Resultsmentioning

confidence: 99%

Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification

Valentijn

Koster

Haneveld

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

220

254

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Neuroblastoma is a pediatric tumor of the sympathetic nervous system. MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is amplified in 20% of neuroblastomas, and these tumors carry a poor prognosis. However, tumors without MYCN amplification also may have a poor outcome. Here, we identified downstream targets of MYCN by shRNA-mediated silencing MYCN in neuroblastoma cells. From these targets, 157 genes showed an expression profile correlating with MYCN mRNA levels in NB88, a series of 88 neuroblastoma tumors, and therefore represent in vivo relevant MYCN pathway genes. This 157-gene signature identified very poor prognosis tumors in NB88 and independent neuroblastoma cohorts and was more powerful than MYCN amplification or MYCN expression alone. Remarkably, this signature also identified poor outcome of a group of tumors without MYCN amplification. Most of these tumors have low MYCN mRNA levels but high nuclear MYCN protein levels, suggesting stabilization of MYCN at the protein level. One tumor has an MYC amplification and high MYC expression. Chip-on-chip analyses showed that most genes in this signature are directly regulated by MYCN. MYCN induces genes functioning in cell cycle and DNA repair while repressing neuronal differentiation genes. The functional MYCN-157 signature recognizes classical neuroblastoma with MYCN amplification, as well as a newly identified group marked by MYCN protein stabilization. N euroblastoma is a pediatric solid tumor derived from the sympathetic nervous system. The prognosis is highly variable and is associated with parameters such as age at diagnosis, dissemination at time of diagnosis, tumor stage, and grade of differentiation of the primary tumor (1). Neuroblastoma stages 1 and 2 have a very good prognosis, but survival in stage 4 neuroblastoma is below 30%. Amplification of MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is associated with poor outcome. It occurs in about 20% of the tumors but is confined to high-stage neuroblastoma.Together with MYC and MYCL, MYCN belongs to the MYC transcription factor family, whose role in cancer has been studied extensively. A series of investigators have manipulated MYCN expression in neuroblastoma cell lines by overexpression or silencing. High expression of MYCN is associated with fast proliferation and induction of cell cycle genes [(2-5) and reviewed by Bell (5)]. Although cell cycle genes were identified, the actual number of MYC-regulated genes is a small minority compared with all other genes claimed to be regulated in such experiments. In fact, thousands of candidate target genes of MYC and/or MYCN currently are known, which has complicated pinpointing of the relevant set of genes regulated by MYC genes and responsible for the aggressive phenotype.In a very early study, MYCN protein expression was found to be a poor prognostic factor (6). Recent experiments in cell lines showed that MYCN protein stability is decreased after phosphorylation by glycogen synthas...

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“…These complexes also bind to E-box elements, but repress transcription through the recruitment of corepressors (11). Through interaction with Sp1 and Miz-1 at promoters, N-myc has been shown to silence gene expression by recruitment of the histone deacetylase HDAC1 (12,13).…”

Section: Introductionmentioning

confidence: 99%

N-myc and Noncoding RNAs in Neuroblastoma

Buechner

Einvik

2012

Molecular Cancer Research

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Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Amplification and overexpression of the MYCN proto-oncogene occurs in approximately 20% of neuroblastomas and is associated with advanced stage disease, rapid tumor progression, and poor prognosis. MYCN encodes the transcriptional regulator N-myc, which has been shown to both up-and downregulate many target genes involved in cell cycle, DNA damage, differentiation, and apoptosis in neuroblastoma. During the last years, it has become clear that N-myc also modulates the expression of several classes of noncoding RNAs, in particular microRNAs. MicroRNAs are the most widely studied noncoding RNA molecules in neuroblastoma. They function as negative regulators of gene expression at the posttranscriptional level in diverse cellular processes. Aberrant regulation of miRNA expression has been implicated in the pathogenesis of neuroblastoma. While the N-myc protein is established as an important regulator of several miRNAs involved in neuroblastoma tumorigenesis, tumor suppressor miRNAs have also been documented to repress MYCN expression and inhibit cell proliferation of MYCN-amplified neuroblastoma cells.

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A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at theTRKAandp75NTRPromoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGF

Cited by 87 publications

References 36 publications

A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma

A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma

Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification

N-myc and Noncoding RNAs in Neuroblastoma

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