The COP9 signalosome subunit CSN1 regulates glioblastoma stem cell growth.

Abstract

The COP9 signalosome is composed of 8 subunits (CSN1-CSN8) and plays a key role in regulating the activity of the ubiquitin-proteasome system by modulating Cullin-RING ubiquitin ligases. While the function of the COP9 signalosome in regulating protein homeostasis is well established, little is known about its role in glioblastoma. Here, using patient-derived glioblastoma stem cell lines, we identified CSN1 as a crucial COP9 signalosome subunit for in vitro growth. CSN1 knockout was further found to significantly extend survival in orthotopic glioblastoma xenograft models. Transcriptomic analysis revealed that CSN1 knockout disrupted transcriptional programs involved in cell cycle progression and activated apoptotic pathways. Molecular analysis further determined that CSN1 is required for COP9 signalosome complex assembly and regulates AP-1 activation via JNK1/2/3 and c-Jun phosphorylation. These results highlight the essentiality of CSN1 for glioblastoma stem cell growth and provide insights into the cellular mechanisms controlled by CSN1 and the COP9 signalosome.