Abstract
Glioblastoma (GBM; grade 4 glioma) is a highly aggressive and incurable tumor. GBM has recently been characterized as highly dependent on alternative splicing, a critical driver of tumor heterogeneity and plasticity. Estrogen-related receptor β (ERR-β) is an orphan nuclear receptor expressed in the brain, where alternative splicing of the 3' end of the pre-mRNA leads to the production of 3 validated ERR-β protein products: ERR-β short form (ERR-βsf), ERR-β2, and ERR-β exon 10 deleted. Our prior studies have shown the ERR-β2 isoform to play a role in G2/M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERR-βsf isoform in senescence and G1 cell cycle arrest. In this study, we sought to better define the role of the proapoptotic ERR-β2 isoform in GBM. We show that the ERR-β2 isoform is located not only in the nucleus but also in the cytoplasm. ERR-β2 suppresses GBM cell migration and interacts with the actin nucleation-promoting factor cortactin, and an ERR-β agonist is able to remodel the actin cytoskeleton and similarly suppress GBM cell migration. We further show that inhibition of the splicing regulatory cdc2-like kinases in combination with an ERR-β agonist shifts isoform expression in favor of ERR-β2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.-Tiek, D. M., Khatib, S. A., Trepicchio, C. J., Heckler, M. M., Divekar, S. D., Sarkaria, J. N., Glasgow, E., Riggins, R. B. Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma.
Highlights
Glioblastoma (GBM; grade 4 glioma) is a highly aggressive tumor, incurable, and markedly resistant to most systemic chemotherapies
Patient-derived xenografts (PDXs) from primary tumors have been established to address this limitation, and we show that ERRβ2 and ERRβ short form (ERRβsf) protein are broadly expressed across PDX specimens representative of multiple GBM molecular subtypes and clinical/pathological features (Figure 1E, Supplementary Table 1)
The cytoplasmic and nuclear ERRβ2 isoform is expressed in multiple GBM cell lines, PDX
Summary
Glioblastoma (GBM; grade 4 glioma) is a highly aggressive tumor, incurable, and markedly resistant to most systemic chemotherapies. Development of TMZ-resistance is rapid, which is in part due to re-expression of O6-methylguanine methyltransferase (MGMT), the DNA repair enzyme which removes TMZinduced O6-methylguanine DNA adducts. Median survival is only ~14-16 months with TMZ, and after resistance has developed there is no established second-line regimen [1, 2]. This is due in part to our limited understanding of the molecular drivers of GBM, and the inherent challenge of developing effective therapeutic strategies that penetrate the blood brain barrier (BBB). Even when the bulk of the tumor is surgically resected, chemotherapeutic options to target residual disease are limited by the BBB [3], which has severely limited repurposing of drugs from other cancers for GBM
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