MYC stimulates EZH2 expression by repression of its negative regulator miR-26a

Sander, Sandrine; Bullinger, Lars; Klapproth, Kay; Fiedler, Katja; Kestler, Hans A.; Barth, Thomas F.E.; Möller, Peter; Stilgenbauer, Stephan; Pollack, Jonathan R.; Wirth, Thomas

doi:10.1182/blood-2008-03-147645

Cited by 370 publications

(332 citation statements)

References 45 publications

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“…The functional overlap between MYCN and c-MYC is further substantiated by the identification of a c-MYC-translocated neuroblastoma tumor with a mRNA, miRNA and genomic profile that is typical for a MYCN-amplified tumor. It is also perfectly in line with previous reports on miRNAs commonly regulated by c-MYC and MYCN (Chen and Stallings, 2007;Chang et al, 2008;Sander et al, 2008;Schulte et and with the observation that MYCN can functionally replace c-MYC in murine development (Malynn et al, 2000). Whether c-MYC is capable of replacing MYCN remains to be determined but could further corroborate these findings.…”

Section: Discussionsupporting

confidence: 91%

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYCand MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/ MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/ MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/ MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis.

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Section: Discussionsupporting

confidence: 91%

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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“…It is not fully established how MYCBP regulates these E-box-containing genes because of growing evidence about the function of MYCBP (Furusawa et al, 2001Yukitake et al, 2002;Ishizaki et al, 2006), but there is evidence suggesting that MYCBP acts, at least in part, through modulating the transactivation activity of c-Myc to enhance the transcription of these genes (Taira et al, 1998;Sakamuro and Prendergast, 1999). Recent studies showed that some c-Myc-mediated miRNAs were implicated in tumorigenesis, embryonic stem cell differentiation and glutamine metabolism (He et al, 2005;O'Donnell et al, 2005;Dews et al, 2006;Chang et al, 2008;Sander et al, 2008;Gao et al, 2009;Lin et al, 2009;Mestdagh et al, 2009). However, only two miRNAs were found to modulate c-Myc, whereas c-Myc is not their significant targets (Sampson et al, 2007;Lal et al, 2009).…”

Section: Mir-22 Might Constitute a Feedback Loop With C-myc And Mycbpmentioning

confidence: 99%

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

2010

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Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Mycbinding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3 0 -untranslational region (3 0 UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.

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“…In humans, the LET-7 has been shown to act as a tumour suppressor, via targeting the human RAS oncogene (40)(41)(42)(43). Similarly, as explained previously, miR-26A also acts in a tumour suppressor capacity (18,38,39,47). Evaluation of the role of these miRs in B-cell lymphoma pathogenesis merits further investigation.…”

Section: Discussionmentioning

confidence: 58%

“…tures of both entities included up-regulated microRNAs of the known oncomiR miR-17-92 (27) as well as downregulated microRNAs recognised as tumour suppressors, including miR-26A (38,39) and members of the the LET-7 family (40)(41)(42)(43). Thus, these signatures correctly predicted the prognostic significance assigned to the immunophenotype, especially that of the ABC-type.…”

Section: Discussionmentioning

confidence: 96%

“…The significant differences in miR-26A expression between the tumour groups and between normal and malignant cells suggest a role for this microRNA in the pathogenesis of B-cell lymphoma. miR-26A has recently been identified as a potential tumour suppressor, via its ability to attenuate proliferation in c-MYC-dependent cells (39). In addition, miR-26A can influence the cell cycle, by repressing cyclins D2 and E2 (38) and also via targeting the EZH2 oncogene, a global regulator of gene expression (39).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A 9 series microRNA signature differentiates between germinal centre and activated B-cell-like diffuse large B-cell lymphoma cell lines

Culpin

Proctor²,

Angus³

et al. 2010

Int J Oncol

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Abstract.The microRNAs are endogenous, non-coding RNAs that play key roles in a range of pathophysiological processes by up-or down-regulating gene expression. Recent studies have shown that some microRNAs have oncogenic or tumour suppressor activity. Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin's lymphoma with a heterogeneous biology, which has impeded the clinical assessment of patients. The currently-used clinically-based IPI provides useful information for treatment decision making, but has limited predictive power. Recent immunohistochemical approaches have identified two different prognostic groups: the more indolent germinal centre (GC)-and the higher risk activated B-cell (ABC)-like phenotypes. Although useful, prediction based on immunophenotype has limitations. The present study uses microRNA profiling and a number of well-characterised B-cell lymphoma cell lines to identify microRNA signatures that are correctly assigned to the DLBCL prognostic subgroups and distinguish DLBCL from other more indolent lymphoma, including follicular lymphoma (FL). MicroRNA microarray analysis was based on miRBase version 12.0 and analysis was performed using an unsupervised hierarchical clustering model. Discriminatory microRNAs were validated by qRT-PCR. We identified a 9 microRNA signature that discriminated between ABC-and GC-like DLBCL. This included 3 newly identified microRNAs, not previously associated with DLBCL and predicted to target genes that are de-regulated in lymphoma. DLBCL was distinguished from FL by 4 microRNAs and a total of 18 microRNAs were identified that differentiated between all lymphoma and control populations. Most of the discriminatory microRNAs have been reported previously to be known oncomiRs or act as tumour suppressors. In conclusion, the present study identified a microRNA signature that correctly classified GC and ABC phenotypes in DLBCL cell lines. This signature has yet to be assessed for prediction in clinical samples.

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MYC stimulates EZH2 expression by repression of its negative regulator miR-26a

Abstract: The MYC oncogene, which is commonly mutated/amplified in tumors, represents an important regulator of cell growth because of its ability to induce both proliferation and apoptosis.

Cited by 370 publications

References 45 publications

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

A 9 series microRNA signature differentiates between germinal centre and activated B-cell-like diffuse large B-cell lymphoma cell lines

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