The Putative Tumor Suppressor microRNA-101 Modulates the Cancer Epigenome by Repressing the Polycomb Group Protein EZH2

Friedman, Jeffrey M.; Liang, Gangning; Liu, Chun-Chi; Wolff, Erika M.; Tsai, Yvonne; Ye, Wei; Zhou, Xianghong Jasmine; Jones, Peter A.

doi:10.1158/0008-5472.can-08-3114

Cited by 362 publications

(283 citation statements)

References 34 publications

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“…Reintroduction of miR-101 but not miR-29c or miR-26a in ALK + ALCL cell lines attenuated cell proliferation. Described and validated targets for miR-101 include mTOR (31), the antiapoptotic protein Mcl1 (39), and the histone methyltransferase EZH2 (40,41). In support of our data, Mcl1 and EZH2 have been reported as overexpressed in ALK + ALCL as well as in ALK − ALCL (8,33,42).…”

Section: Discussionsupporting

confidence: 82%

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Merkel

Hamacher

Laimer

et al. 2010

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

106

133

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Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101

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Section: Discussionsupporting

confidence: 82%

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Merkel

Hamacher

Laimer

et al. 2010

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

106

133

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“…Estrogen affects miR-101-mediated cell growth and Akt activation Previously, miR-101 had been shown to be a tumor suppressor capable of inhibiting cell growth (Varambally et al, 2008;Friedman et al, 2009). In support of these findings, cell proliferation assays also indicated that miR-101 had a negative effect on cell growth in normal E2-containing medium ( Figure 3a).…”

Section: Enrichment Of Micrornas Required For Estrogen Independency Bsupporting

confidence: 69%

MicroRNA-101-mediated Akt activation and estrogen-independent growth

Sachdeva

et al. 2010

Oncogene

110

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MicroRNAs are gene regulators that work through a posttranscriptional repression mechanism. Dysregulation of microRNA expression could lead to a variety of disorders, in particular, human cancer, and has also been implicated in antihormone therapy resistance. However, little is known whether microRNAs have a role in estrogen-independent growth, leading to tamoxifen resistance in estrogen receptor (ER)-positive tumors. In this study, we use an in vivo selection system against a microRNA library using the MCF-7 model and demonstrate that miR-101 promotes estrogen-independent growth and causes the upregulation of phosphorylated Akt (pAkt) without impacting the ER level or activity. Importantly, although miR-101 suppresses cell growth in normal estradiol (E2)-containing medium, it promotes cell growth in E2-free medium. Moreover, estrogen deprivation greatly enhances miR-101-mediated Akt activation. Finally, we show that MAGI-2 (membrane-associated guanylate kinase), a scaffold protein required for PTEN (phosphatase and tensin homolog) activity, is a direct target for miR-101; suppression of MAGI-2 by miR-101 reduces PTEN activity, leading to Akt activation. Taken together, these results not only establish a role for miR-101 in estrogen-independent signaling but also provide a mechanistic link between miR-101 and Akt activation.

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“…miR-148 repressed expression of DNMT3B through binding with high homology to the region of the coding sequence of the DNMT3B transcript, but the mechanism remained unclear. In contrast to miR-148a, miR-101 modulates cancer epigenetics by repressing the polycomb group protein EZH2, which contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells (Varambally et al, 2008;Friedman et al, 2009). Not only does miR-101 suppress the expression and function of EZH2 in cancer cell lines but also there is an inverse correlation between miR-101 expression and EZH2 expression during cancer progression in human prostate tumors (Varambally et al, 2008).…”

Section: Microrna and Metastasis H Zhang Et Almentioning

confidence: 99%

The microRNA network and tumor metastasis

2009

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Metastasis is the most significant process affecting the clinical management of cancer patients and occurs in multiple sequential steps. However, the molecular pathways underlying each step still remain obscure. Recent research has shown that there is a microRNA (miRNA) network that functions as a regulator of tumor metastasis. In this paper, we review the role of miRNAs in tumor metastasis, including control of epithelial-mesenchymal transition, regulation of metastasis-associated genes and epigenetic alterations. More information on miRNAs will promote a better understanding of the molecular mechanism of metastasis.

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The Putative Tumor Suppressor microRNA-101 Modulates the Cancer Epigenome by Repressing the Polycomb Group Protein EZH2

Cited by 362 publications

References 34 publications

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

MicroRNA-101-mediated Akt activation and estrogen-independent growth

The microRNA network and tumor metastasis

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The Putative Tumor Suppressor microRNA-101 Modulates the Cancer Epigenome by Repressing the Polycomb Group Protein EZH2

Cited by 362 publications

References 34 publications

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+and ALK−anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+and ALK−anaplastic large-cell lymphoma

MicroRNA-101-mediated Akt activation and estrogen-independent growth

The microRNA network and tumor metastasis

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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma