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 an aggressive and incurable tumor characterized by extensive heterogeneity and plasticity, in part due to its reliance on alternative splicing. Estrogen-related receptor β (ERR-β), an orphan nuclear receptor expressed in the brain, undergoes alternative splicing at the 3′ end of its pre-mRNA, generating three validated protein isoforms: ERR-β short form (ERR-βsf), ERR-β2, and ERR-β exon 10 deleted. Our previous studies identified ERR-β2 as a key regulator of G2/M cell cycle arrest and apoptosis, whereas ERR-βsf primarily mediates senescence and G1 cell cycle arrest. In this study, we further investigate TG003 the role of ERR-β2 in GBM. We demonstrate that ERR-β2 localizes to both the nucleus and cytoplasm, suppresses GBM cell migration, and interacts with cortactin, an actin nucleation-promoting factor. Additionally, treatment with an ERR-β agonist remodels the actin cytoskeleton and similarly inhibits GBM cell migration. Moreover, inhibition of splicing regulatory cdc2-like kinases, in combination with ERR-β activation, shifts isoform expression toward ERR-β2, enhancing the suppression of GBM cell growth and migration both in vitro and in intracranial tumor models.