RT Journal Article
SR Electronic
T1 A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.03.469255
DO 10.1101/2021.12.03.469255
A1 Wan-Hsin Lin
A1 Ryan W. Feathers
A1 Lisa M. Cooper
A1 Laura J. Lewis-Tuffin
A1 Jann N. Sarkaria
A1 Panos Z. Anastasiadis
YR 2021
UL http://biorxiv.org/content/early/2021/12/03/2021.12.03.469255.abstract
AB Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic GBM patient-derived xenografts. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due at least in part to increased cytoplasmic retention and reduced activity of the YAP/TAZ transcriptional coactivators. Further, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells irrespective of their inherent response to TMZ. Taken together, the data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.One Sentence Summary Syx promotes growth and therapy resistance in glioblastoma.Competing Interest StatementThe authors have declared no competing interest.