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.
Keywords: CLK; ERR-β; GBM; alternative splicing; cortactin.