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Cited by 62Hippo pathway signaling and YAP/TAZGlioma Diagnosis and TreatmentProtein Kinase Regulation and GTPase Signaling

YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity

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Yu, Olivia M., Benitez, Jorge A., Plouffe, Steven W., Ryback, Daniel, Klein, Andrea, Smith, Jeff, Greenbaum, Jason, Delatte, Benjamin +6 more·2018·Oncogene
DOI 10.1038/s41388-018-0301-5PMC PMC6195840
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Abstract

The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.

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Authors
Yu, O. M., Benitez, J. A., Plouffe, S. W., Ryback, D., Klein, A., Smith, J., Greenbaum, J., Delatte, B., Rao, A., Guan, K.-L., Furnari, F. B., Chaim, O. M., Miyamoto, S., & Brown, J. H.
Affiliations
  • University of California San Diego (US)
  • La Jolla Institute for Immunology (US)
  • Ludwig Cancer Research (BE)
Corresponding author
Brown, Joan Heller
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2018-06-11
Volume
37
Issue
41
Pages
5492-5507
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/s41388-018-0301-5
PMC
PMC6195840
OpenAlex
W2806328383
Cited by
62
References
5
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 16 · 2020: 12 · 2019: 8 · 2018: 2
FWCI
5.20
Type
journal article
Language
en
Update notices
expression_of_concern (2026-04-21)
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Institutes of Health (HL028143, NS080939, HL097037, HL-085577, GM036927, AI109842)
  • National Heart, Lung, and Blood Institute (P01HL085577, R01HL097037, R56HL097037, R37HL028143, R01HL028143)
  • National Cancer Institute (R01CA218859, R35CA196878)
  • National Institute of General Medical Sciences (R56GM036927, T32GM007752, R01GM036927)
  • National Institute of Allergy and Infectious Diseases (R01AI109842, R56AI109842, R01AI040127)
  • National Institute of Neurological Disorders and Stroke (R01NS080939, R56NS080939)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
YAP, MRTF-A, glioblastoma, RhoA signaling, transcriptional coactivator, G protein-coupled receptors, sphingosine-1-phosphate, cancer stem cells, patient-derived xenografts, tissue factor, HB-EGF, cell migration and invasion, cell adhesion, tumor cell proliferation, self-renewal, oncogene expression
MeSH terms
YAP-Signaling Proteins, Animals, Brain Neoplasms, Glioblastoma, Humans, Mice, Nude, Phosphoproteins, Transcription Factors, Trans-Activators, Gene Expression Regulation, Neoplastic, rhoA GTP-Binding Protein, Adaptor Proteins, Signal Transducing, Mice, Heterografts

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