RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation.

Cell Discov

Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.

Published: March 2024

Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10951364PMC
http://dx.doi.org/10.1038/s41421-024-00654-3DOI Listing

Publication Analysis

Top Keywords

alternative polyadenylation
12
rbbp6 maintains
8
glioblastoma stem
8
stem cells
8
cpsf3-dependent alternative
8
ubiquitin ligases
8
ligases deubiquitinases
8
myc expression
8
rbbp6
6
glioblastoma
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!