OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells

Overview

Journal Cancer Res

Specialty Oncology

Date 2012 Sep 19

PMID 22986744

Citations 25

Authors

Ren-Yuan Bai

Verena Staedtke

Hart G Lidov

Charles G Eberhart

Gregory J Riggins

Affiliations

Soon will be listed here.

Abstract

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. RNA interference-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, 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 medullomyoblastomas and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential.

Citing Articles

Arrested development: the dysfunctional life history of medulloblastoma.

Tao R, Han K, Wu S, Friske J, Roussel M, Northcott P Genes Dev. 2024; 39(1-2):4-17.

PMID: 39231614 PMC: 11789489. DOI: 10.1101/gad.351936.124.

Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma.

Li M, Han Y, Wang C, Kang W, Jiang W, Zhang L J Exp Clin Cancer Res. 2022; 41(1):311.

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The landscape of chromatin accessibility in skeletal muscle during embryonic development in pigs.

Yue J, Hou X, Liu X, Wang L, Gao H, Zhao F J Anim Sci Biotechnol. 2021; 12(1):56.

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Impact of Reck expression and promoter activity in neuronal in vitro differentiation.

Trombetta-Lima M, Assis-Ribas T, Cintra R, Campeiro J, Guerreiro J, Winnischofer S Mol Biol Rep. 2021; 48(2):1985-1994.

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OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements.

Kerschner J, Paranjapye A, Nandymazumdar M, Yin S, Leir S, Harris A Dev Dyn. 2021; 250(5):684-700.

PMID: 33386644 PMC: 11227118. DOI: 10.1002/dvdy.293.

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