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

Deanna M. Tiek, Subreen A. Khatib, Colin J. Trepicchio, Mary M. Heckler, Shailaja D. Divekar, Jann N. Sarkaria, Eric Glasgow, Rebecca B. Riggins

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)13476-13491
Number of pages16
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number12
DOIs
StatePublished - Dec 1 2019

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Glioblastoma
Estrogen Receptors
Tumors
Protein Isoforms
Estrogens
Phosphotransferases
Chemical activation
Growth
Neoplasms
Alternative Splicing
Cell Movement
Actins
Cortactin
Cells
Orphan Nuclear Receptors
G2 Phase Cell Cycle Checkpoints
G1 Phase Cell Cycle Checkpoints
RNA Precursors
Actin Cytoskeleton
Glioma

Keywords

  • alternative splicing
  • CLK
  • cortactin
  • ERR-β
  • GBM

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. / Tiek, Deanna M.; Khatib, Subreen A.; Trepicchio, Colin J.; Heckler, Mary M.; Divekar, Shailaja D.; Sarkaria, Jann N.; Glasgow, Eric; Riggins, Rebecca B.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 12, 01.12.2019, p. 13476-13491.

Research output: Contribution to journalArticle

Tiek, Deanna M. ; Khatib, Subreen A. ; Trepicchio, Colin J. ; Heckler, Mary M. ; Divekar, Shailaja D. ; Sarkaria, Jann N. ; Glasgow, Eric ; Riggins, Rebecca B. / Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 ; Vol. 33, No. 12. pp. 13476-13491.
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AU - Khatib, Subreen A.

AU - Trepicchio, Colin J.

AU - Heckler, Mary M.

AU - Divekar, Shailaja D.

AU - Sarkaria, Jann N.

AU - Glasgow, Eric

AU - Riggins, Rebecca B.

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AB - 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.

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