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Series GSE268563 Query DataSets for GSE268563
Status Public on Jun 01, 2024
Title Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial 1 homeostasis and increases antitumor activity against glioblastoma
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Background: Few druggable targets have been discovered in glioblastoma (GBM); however, increasing knowledge has uncovered two hallmarks of this disease: epigenetic modifications and cell cycle dysregulation. Methods: Here, we investigated the effects of the EZH2 inhibitor GSK126 alone and in combination with the CDK4/6 inhibitor abemaciclib on morphology, growth, invasiveness, protein and gene expression, mitochondrial function, and induction of cell death in patient-derived GBM cells (GBM03, GBM06, GBM14, and GBM15). Results: EZH2 expression, CDK4 amplification, and CDKN2A deletion were first confirmed. The combined use of GSK126 and abemaciclib resulted in synergistic effects in all patient-derived GBM cell lines. After treatment, the cells appeared swollen with a large flat cytoplasm and cellular stress fibers due to HIF1 upregulation and CalR translocation. Notably, abemaciclib-induced cellular stemness (NANOG+, OCT3/4+, and SOX2+) was antagonized by this combination treatment. The MitoStress Test revealed a massive impairment of mitochondrial function. The basal oxygen consumption rate, ATP synthesis, and maximal respiration of the mitochondria decreased, confirming reduced cellular fitness and disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by massive mitochondrial ROS production leading to mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6, and IRE1. Spheroid invasion was reduced in 3/4 cases, again with synergistic effects after dual EZH2 and CDK4/6 blockade. Differentially expressed genes involved mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), and a shift in the stemness profile towards a more differentiated state. Notably, the antitumor effect was partially confirmed in ovo as well as in patient-derived organoids. Conclusions: We propose dual blocking of GBM hallmarks as a potential treatment strategy. Biomarker-driven targeted therapies will hopefully guide the development of more refined treatments.
 
Overall design Triplicates of patient derived glioblastoma cells (GBM15), treated with the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib were compared alone and in combination (kombi) with sham controls (DMSO).
 
Contributor(s) Freitag T, Kaps P, Ramtke J, Bertels S, Zunke E, Schneider B, Becker A, Koczan D, Dubinski D, Freiman MT, Wittig F, Hinz B, Westhoff M, Strobel H, Meiners F, Wolter D, Engel N, Troschke-Meuer S, Bergmann-Ewert W, Staehlke S, Wolff A, Gessler F, Junghanss C, Maletzki C
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Submission date May 29, 2024
Last update date Jun 01, 2024
Contact name Dirk Koczan
E-mail(s) dirk.koczan@med.uni-rostock.de
Phone +493814945885
Organization name University of Rostock
Department Institute for Immunology
Street address Schillingallee 70
City Rostock
ZIP/Postal code 18057
Country Germany
 
Platforms (1)
GPL23159 [Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay)
Samples (12)
GSM8294302 GBM15_Abemaciclib_DF1
GSM8294303 GBM15_Abemaciclib_DF2
GSM8294304 GBM15_Abemaciclib_DF3
Relations
BioProject PRJNA1117807

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Supplementary file Size Download File type/resource
GSE268563_RAW.tar 14.5 Mb (http)(custom) TAR (of CEL, CHP)

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