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

FASEB J. 2019 Dec;33(12):13476-13491. doi: 10.1096/fj.201901075R. Epub 2019 Sep 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Animals
  • Apoptosis
  • Biomarkers, Tumor
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / prevention & control*
  • Cell Cycle
  • Cell Movement*
  • Cell Proliferation
  • Drug Therapy, Combination
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / prevention & control*
  • Humans
  • Hydrazines / pharmacology*
  • Protein Isoforms
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Thiazoles / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Zebrafish


  • Biomarkers, Tumor
  • ESRRB protein, human
  • Hydrazines
  • N'-((1E)-(4-(diethylamino)phenyl)methylene)-4-hydroxybenzohydrazide
  • Protein Isoforms
  • Receptors, Estrogen
  • TG 003
  • Thiazoles
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases