PUBLICATION
Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma
- Authors
- Tiek, D.M., Khatib, S.A., Trepicchio, C.J., Heckler, M.M., Divekar, S.D., Sarkaria, J.N., Glasgow, E., Riggins, R.B.
- ID
- ZDB-PUB-200610-12
- Date
- 2019
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33: 13476-13491 (Journal)
- Registered Authors
- Glasgow, Eric
- Keywords
- CLK, ERR-β, GBM, alternative splicing, cortactin
- 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
- PubMed
- 31570001 Full text @ FASEB J.
Citation
Tiek, D.M., Khatib, S.A., Trepicchio, C.J., Heckler, M.M., Divekar, S.D., Sarkaria, J.N., Glasgow, E., Riggins, R.B. (2019) Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 33:13476-13491.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping