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Updated: Jun 30, 2025

Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
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Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells

Published on: September 1, 2010

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RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation

Peng Lin1,2,3, Wenyan Chen4, Zhilin Long2,3

  • 1College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Cell Discovery
|March 20, 2024
PubMed

Insights

RBBP6 is crucial for glioblastoma stem cell survival and tumor growth. Targeting RBBP6 or CPSF3 inhibits glioblastoma, offering new therapeutic strategies for this lethal brain cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Glioblastoma is a highly lethal brain cancer characterized by significant intratumor heterogeneity.
  • Glioblastoma stem cells (GSCs) play a critical role in glioblastoma development and resistance to therapy.
  • Ubiquitin ligases and deubiquitinases are emerging therapeutic targets in cancer.

Purpose of the Study:

  • To identify essential ubiquitinating enzymes for glioblastoma stem cell maintenance using large-scale genetic screens.
  • To elucidate the molecular mechanisms by which identified targets regulate GSC function.
  • To evaluate the therapeutic potential of targeting these mechanisms in glioblastoma.

Main Methods:

  • Conducted parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases.
  • Investigated the role of the identified E3 ligase, RBBP6, in GSC proliferation and tumor initiation.
  • Analyzed the mechanism involving RBBP6, Cleavage and Polyadenylation Specific Factor 3 (CPSF3) ubiquitination, and alternative polyadenylation.
  • Assessed the impact of targeting RBBP6 and CPSF3 (using JTE-607) on GSC viability and tumor growth.

Main Results:

  • RBBP6 was identified as an essential E3 ligase for glioblastoma stem cell maintenance.
  • Targeting RBBP6 significantly inhibited GSC proliferation and tumor initiation.
  • RBBP6 stabilizes CPSF3 through K63-linked ubiquitination, regulating alternative polyadenylation.
  • RBBP6 depletion leads to shortened 3'UTRs of MYC competing-endogenous RNAs, decreasing MYC expression via miR-590-3p release.
  • Inhibition of CPSF3 with JTE-607 reduced GSC viability and inhibited tumor growth in vivo.

Conclusions:

  • RBBP6 is a key regulator of glioblastoma stem cell maintenance by controlling MYC expression through CPSF3-dependent alternative polyadenylation.
  • Targeting RBBP6 or CPSF3 presents a promising therapeutic strategy for glioblastoma treatment.

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