TY - JOUR
T1 - Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma
AU - Tiek, Deanna M.
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.
N1 - Funding Information:
The authors thank members of the R.B.R. laboratory, as well as Drs. Maria Laura Avantaggiati, Deborah Berry, Karen Creswell, Brent Harris, Peter Johnson, Supti Sen, Alexandra Taraboletti, Jeffrey Toretsky, Todd Waldman, and Dan Xun (Lombardi Comprehensive Cancer Center, Georgetown University) for sharing reagents, scientific insights, technical assistance, and/or editorial comments on the manuscript. This work was supported by U.S. National Institutes of Health/National Cancer Institute Grant (NIH/NCI) R21 CA191444 (to R.B.R.), a Georgetown University Medical Center (GUMC) Dean for Research's Toulmin Pilot Project Award (to R.B.R.), and a Partners in Research Breakthrough Award (to R.B.R.), as well as NIH/NCI Grant F99 CA234799 (to D.M.T.) and a student research grant from the Medical Center Graduate Student Organization (MCGSO; to D.M.T.). Additional fellowship funding for D.M.T. and M.M.H. was provided by the Tumor Biology Training Grant [T32 CA009686, principal investigator (PI): Dr. Anna T. Riegel]. Technical services were provided by the GUMC Animal Models, Flow Cytometry and Cell Sorting, Histopathology and Tissue, Microscopy and Imaging, and Tissue Culture Shared Resources, which are supported, in part, by NIH/NCI Cancer Center Support Grant P30 CA051008 (PI: Dr. Louis M. Weiner). The Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource is supported, in part, by P50 CA108961 (to J.N.S., PI: Dr. Patrick O'Neill). The content of this article is the sole responsibility of the authors and does not represent the official views of the NIH. The authors declare no conflicts of interest.
Funding Information:
The authors thank members of the R.B.R. laboratory, as well as Drs. Maria Laura Avantaggiati, Deborah Berry, Karen Creswell, Brent Harris, Peter Johnson, Supti Sen, Alexandra Taraboletti, Jeffrey Toretsky, Todd Waldman, and Dan Xun (Lombardi Comprehensive Cancer Center, Georgetown University) for sharing reagents, scientific insights, technical assistance, and/or editorial comments on the manuscript. This work was supported by U.S. National Institutes of Health/National Cancer Institute Grant (NIH/NCI) R21 CA191444 (to R.B.R.), a Georgetown University Medical Center (GUMC) Dean for Research's Toulmin Pilot Project Award (to R.B.R.), and a Partners in Research Breakthrough Award (to R.B.R.), as well as NIH/NCI Grant F99 CA234799 (to D.M.T.) and a student research grant from the Medical Center Graduate Student Organization (MCGSO; to D.M.T.). Additional fellowship funding for D.M.T. and M.M.H. was provided by the Tumor Biology Training Grant [T32 CA009686, principal investigator (PI): Dr. Anna T. Riegel]. Technical services were provided by the GUMC Animal Models, Flow Cytometry and Cell Sorting, Histopathology and Tissue, Microscopy and Imaging, and Tissue Culture Shared Resources, which are supported, in part, by NIH/NCI Cancer Center Support Grant P30 CA051008 (PI: Dr. Louis M. Weiner). The Mayo Clinic Brain Tumor Patient‐Derived Xenograft National Resource is supported, in part, by P50 CA108961 (to J.N.S., PI: Dr. Patrick O'Neill). The content of this article is the sole responsibility of the authors and does not represent the official views of the NIH. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2019/12
Y1 - 2019/12
N2 - 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. FASEB J. 33, 13476–13491 (2019). www.fasebj.org.
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. FASEB J. 33, 13476–13491 (2019). www.fasebj.org.
KW - CLK
KW - ERR-β
KW - GBM
KW - alternative splicing
KW - cortactin
UR - http://www.scopus.com/inward/record.url?scp=85076126157&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076126157&partnerID=8YFLogxK
U2 - 10.1096/fj.201901075R
DO - 10.1096/fj.201901075R
M3 - Article
C2 - 31570001
AN - SCOPUS:85076126157
SN - 0892-6638
VL - 33
SP - 13476
EP - 13491
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -