Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt, Jens; Haas, Talitha G. de; Hasselt, Nancy E.; Zwijnenburg, Danny; Koster, Jan; Versteeg, Rogier; Kool, Marcel

doi:10.1158/1541-7786.mcr-09-0546

Cited by 45 publications

(56 citation statements)

References 52 publications

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“…Identifying the feedback circuits that link the upstream and downstream regulation of this miRNA cluster will be informative. Indeed, there is marked conservation of the upstream regulatory region of the miR-183 cluster and prior ChIP–on-chip analyses have shown enrichment of this promoter region upon immunoprecipitation of the medulloblastoma oncogene, OTX2 [5] (M. Kool, personal communication). At a minimum, incorporation of mTOR inhibitors as a treatment or adjuvant for medulloblastomas expressing miR-183∼96∼182 should be considered.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

et al. 2012

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Medulloblastomas are the most common malignant brain tumors in children. Several large-scale genomic studies have detailed their heterogeneity, defining multiple subtypes with unique molecular profiles and clinical behavior. Increased expression of the miR-183∼96∼182 cluster of microRNAs has been noted in several subgroups, including the most clinically aggressive subgroup associated with genetic amplification of MYC. To understand the contribution of miR-183∼96∼182 to the pathogenesis of this aggressive subtype of medulloblastoma, we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells. Knockdown of the full miR-183∼96∼182 cluster results in enrichment of genes associated with apoptosis and dysregulation of the PI3K/AKT/mTOR signaling axis. Conversely, there is a relative enrichment of pathways associated with migration, metastasis and epithelial to mesenchymal transition, as well as pathways associated with dysfunction of DNA repair in cells with preserved miR-183 cluster expression. Immunocytochemistry and FACS analysis confirm induction of apoptosis upon knockdown of the miR-183 cluster. Importantly, cell-based migration and invasion assays verify the positive regulation of cell motility/migration by the miR-183 cluster, which is largely mediated by miR-182. We show that the effects on cell migration induced by the miR-183 cluster are coupled to the PI3K/AKT/mTOR pathway through differential regulation of AKT1 and AKT2 isoforms. Furthermore, we show that rapamycin inhibits cell motility/migration in medulloblastoma cells and phenocopies miR-183 cluster knockdown. Thus, the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma.

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Section: Discussionmentioning

confidence: 99%

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

et al. 2012

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“…The expression of OTX2 is low or absent in Shh-driven human medulloblastoma (17,18). OTX2 copy number gain has been associated with more aggressive tumor phenotypes and decreased patient survival (18), and inhibition of OTX2 in medulloblastoma cell lines decreased tumor proliferation and formation in vitro (19). It is currently unclear whether modest upregulation of OTX2 is related to saridegib resistance.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model

Lee

Hatton

Villavicencio

et al. 2012

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

116

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The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

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“…Additionally, knockdown by OTX2 siRNA or suppression of OTX2 promoter by 9-cis retinoic acid slowed medulloblastoma tumor growth in mice (5, 19), suggesting that OTX2 expression sustains tumor growth. Recently, Bunt et al reported that induced over-expression of OTX2 in MB cells leads to G1 arrest in cell cycle and senescence-like phenotype (20), while, however, an inducible knockdown of OTX2 activated cell cycle regulators and neuronal genes (21). Beside genomic amplification as a means of OTX2 activation, the majority of medulloblastomas overexpress OTX2 through an unknown mechanism.…”

Section: Introductionmentioning

confidence: 99%

OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells

et al. 2012

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The brain development transcription factor OTX2 is overexpressed and/or genomically amplified in most medulloblastomas, but the mechanistic basis for its contributions in this setting are not understood. In this study we identified OTX2 as a transcriptional repressor and a gatekeeper of myogenic and neuronal differentiation in medulloblastoma cells. OTX2 binds to the MyoD1 core enhancer through its homeobox domain and the remarkable repressor activity exhibited by the homeobox domain renders OTX2 transcriptionally repressive. RNAi-mediated attenuation of OTX2 expression triggered myogenic and neuronal differentiation in vitro and prolonged the survival in an orthotopic medulloblastoma mouse model. Conversely, inducing myogenic conversion of medulloblastoma cells led to the loss of OTX2 expression. In medullomyoblastoma (MMB), a medulloblastoma subtype containing muscle elements, myogenic cells share cytogenetic signatures with the primitive tumor cells and OTX2 expression was lost in the differentiated myogenic cells. Thus, OTX2 functions via its homeobox domain as a suppressor of differentiation and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. Together, our findings illustrate the origin of muscle cells in MMBs and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential.

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Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Cited by 45 publications

References 52 publications

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model

OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells

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