Oncogenic transgelin-2 is differentially regulated in isocitrate dehydrogenase wild-type vs. mutant gliomas.

Sasha J Beyer,Arnab Chakravarti,Jessica L Fleming,Anca L Grosu,Ilinca Popp,Benjamin Johnson,Ori Staszewski,Erica H Bell,Saikh Jaharul Haque,Aline Becker,Joseph P Mcelroy,Emily Bassett,Pooja Gulati,Tiantian Cui,Marco Prinz

doi:10.18632/oncotarget.26365

Sasha J Beyer, Arnab Chakravarti + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.26365

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Journal: Oncotarget	Publication Date: Dec 14, 2018
Citations: 5	License type: cc-by

Affiliation: The Ohio State University, University of Freiburg

Abstract

The presence of an isocitrate dehydrogenase (IDH1/2) mutation in gliomas is associated with favorable outcomes compared to gliomas without the mutation (IDH1/2 wild-type, WT). The underlying biological mechanisms accounting for improved clinical outcomes in IDH1/2 mutant gliomas remain poorly understood, but may, in part, be due to the glioma CpG island methylator phenotype (G-CIMP) and epigenetic silencing of genes. We performed profiling of IDH1/2 WT versus IDH1/2 mutant Grade II and III gliomas and identified transgelin-2 (TAGLN2), an oncogene and actin-polymerizing protein, to be expressed at significantly higher levels in IDH1/2 WT gliomas compared to IDH1/2 mutant gliomas. This differential expression of TAGLN2 was primarily due to promoter hypermethylation in IDH1/2 mutant gliomas, suggesting involvement of TAGLN2 in the G-CIMP. Our results also suggest that TAGLN2 may be involved in progression due to higher expression in glioblastomas compared to IDH1/2 WT gliomas of lower grades. Furthermore, our results suggest that TAGLN2 functions as an oncogene by contributing to proliferation and invasion when overexpressed in IDH1/2 WT glioma cells. Taken together, this study demonstrates a possible link between increased TAGLN2 expression, invasion and poor patient outcomes in IDH1/2 WT gliomas and identifies TAGLN2 as a potential novel therapeutic target for IDH1/2 WT gliomas.

Highlights

Grade IV glioblastomas (GBM) demonstrate dismal prognoses due to their aggressive nature and resistance to standard of care therapies
TAGLN2 was not included in the reverse-phase protein lysate array (RPPA) used in the The Cancer Genome Atlas (TCGA) analysis and TAGLN2 protein levels could not be validated in tumors from the TCGA cohort [8]
While in agreement with a recent study showing that TAGLN2 is a poor prognostic marker for gliomas, our study is the first to report that TAGLN2 is a negative prognostic factor associated with IDH1/2 WT gliomas and its regulation in gliomas is highly dependent on IDH1/2 mutation status

Summary

Introduction

Grade IV glioblastomas (GBM) demonstrate dismal prognoses due to their aggressive nature and resistance to standard of care therapies. In 2008, the IDH1/2 mutation was discovered in gliomas [3] and has been associated with improved prognoses in gliomas independent of tumor grade (Grade II-IV) or histologic subtype (astrocytoma, oligodendroglioma, oligoastrocytoma) [4]. The World Health Organization (WHO) revised the low(er) grade glioma (LGG) classification system in 2016 to include www.oncotarget.com isocitrate dehydrogenase (IDH1/2) mutations and 1p/19q co-deletion status in addition to glioma grade and histology [5]. IDH1/2 mutation status is routinely being utilized in the clinic to help predict tumor prognosis and guide management decisions for glioma patients [6]. While IDH1/2 mutations most commonly occur in Grade II and III gliomas, they are present in approximately 5% of GBM that have progressed from lower grade gliomas, known as secondary GBM [3, 7]. Secondary GBM patients harboring an IDH1/2 mutation (median survival of 2.1 years) often have improved survival compared to LGG without the mutation, referred to as IDH1/2 wild-type (IDH1/2 WT) (median survival of 1.7 years) [4, 8, 9]

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