Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma

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 beta (ERR-beta) 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-beta protein products: ERR-beta short form (ERR-(beta sf), ERR-beta 2, and ERR-beta exon 10 deleted. Our prior studies have shown the ERR-beta isoform to play a role in G(2)/M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERR-beta 2 isoform in senescence and G1 cell cycle arrest. In this study, we sought to better define the role of the proapoptotic ERR-beta 2 isoform in GBM. We show that the ERR-beta 2 isoform is located not only in the nucleus but also in the cytoplasm. ERR-beta 2 suppresses GBM cell migration and interacts with the actin nucleation-promoting factor cortactin, and an ERR-beta 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-beta agonist shifts isoform expression in favor of ERR-beta 2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.